Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors

ABSTRACT

Aminoguanidine and alkoxyguanidine compounds are described, including compounds of the Formula VII:  
                 
 
     wherein X is O or NR 9  and Het, R 1 , R 7 , R 8 , R 12 -R 15  R a , R b , R c , Z, and n are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin. Also described are methods for preparing such compounds. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.

[0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 60/079,107, filed Mar. 23, 1998, U.S.application Ser. No. 60/067,324, filed Dec. 5, 1997, and U.S.application Ser. No. 60/066,475, filed Nov. 26, 1997, the contents ofall of which are fully incorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to novel compounds that function asproteolytic enzyme inhibitors, and particularly to a new class ofthrombin inhibitors.

[0004] 2. Related Art

[0005] Proteases are enzymes that cleave proteins at single, specificpeptide bonds. Proteases can be classified into four generic classes:serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases(Cuypers et al., J. Biol. Chem. 257:7086 (1982)). Proteases areessential to a variety of biological activities, such as digestion,formation and dissolution of blood clots, reproduction and the immunereaction to foreign cells and organisms. Aberrant proteolysis isassociated with a number of disease states in man and other mammals. Thehuman neutrophil proteases, elastase and cathepsin G, have beenimplicated as contributing to disease states marked by tissuedestruction. These disease states include emphysema, rheumatoidarthritis, corneal ulcers and glomerular nephritis. (Barret, in EnzymeInhibitors as Drugs, Sandler, ed., University Park Press, Baltimore,(1980)). Additional proteases such as plasmin, C-1 esterase, C-3convertase, urokinase, plasminogen activator, acrosin, and kallikreinsplay key roles in normal biological functions of mammals. In manyinstances, it is beneficial to disrupt the function of one or moreproteolytic enzymes in the course of therapeutically treating a mammal.

[0006] Serine proteases include such enzymes as elastase (humanleukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase,urokinase, plasminogen activator, acrosin, chymotrypsin, trypsin,thrombin, factor Xa and kallikreins.

[0007] Human leukocyte elastase is released by polymorphonuclearleukocytes at sites of inflammation and thus is a contributing cause fora number of disease states. Cathepsin G is another human neutrophilserine protease. Compounds with the ability to inhibit the activity ofthese enzymes are expected to have an anti-inflammatory effect useful inthe treatment of gout, rheumatoid arthritis and other inflammatorydiseases, and in the treatment of emphysema. Chymotrypsin and trypsinare digestive enzymes. Inhibitors of these enzymes are useful intreating pancreatitis. Inhibitors of urokinase and plasminogen activatorare useful in treating excessive cell growth disease states, such asbenign prostatic hypertrophy, prostatic carcinoma and psoriasis.

[0008] The serine protease thrombin occupies a central role inhemostasis and thrombosis, and as a multifactorial protein, induces anumber of effects on platelets, endothelial cells, smooth muscle cells,leukocytes, the heart, and neurons. Activation of the coagulationcascade through either the intrinsic pathway (contact activation) or theextrinsic pathway (activation by exposure of plasma to a non-endothelialsurface, damage to vessel walls or tissue factor release) leads to aseries of biochemical events that converge on thrombin. Thrombin cleavesfibrinogen ultimately leading to a hemostatic plug (clot formation),potently activates platelets through a unique proteolytic cleavage ofthe cell surface thrombin receptor (Coughlin, Seminars in Hematology31(4):270-277 (1994)), and autoamplifies its own production through afeedback mechanism. Thus, inhibitors of thrombin function havetherapeutic potential in a host of cardiovascular and non-cardiovasculardiseases.

[0009] Factor Xa is another serine protease in the coagulation pathway.Factor Xa associates with factor Va and calcium on a phospholipidmembrane thereby forming a prothrombinase complex. This prothrombinasecomplex then converts prothrombin to thrombin (Claeson, BloodCoagulation and Fibrinolysis 5:411-436 (1994); Harker, Blood Coagulationand Fibrinolysis 5 (Suppl 1):S47-S58 (1994)). Inhibitors of factor Xaare thought to offer an advantage over agents that directly inhibitthrombin since direct thrombin inhibitors still permit significant newthrombin generation (Lefkovits and Topol, Circulation 90(3):1522-1536(1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58(1994)).

[0010] In vivo diagnostic imaging methods for intravascular thrombi havebeen previously reported. These imaging methods use compounds that aredetectably labeled with radioactive or paramagnetic atoms. For example,platelets labeled with the gamma emitter, In-111, can be employed as animaging agent for detecting thrombi (Thakur, M. L. et al., Thromb Res.9:345 (1976); Powers et al., Neurology 32:938 (1982)). The thrombolyticenzyme streptokinase labeled with Tc-99m has been proposed as an imagingagent (Wong, U.S. Pat. No. 4,418,052 (1983)). The fibrin-binding domainsof Staphylococcus aureus derived protein A labeled with the gammaemitters, I-125 and I-131, have been proposed as imaging agents (Pang,U.S. Pat. No. 5,011,686 (1991)). Monoclonal antibodies havingspecificity for fibrin (in contrast to fibrinogen) and labeled withTc-99m have been proposed as imaging agents (Berger et al., U.S. Pat.No. 5,024,829 (1991); Dean et al., U.S. Pat. No. 4,980,148 (1990)). Theuse of the paramagnetic contrasting agent, gadoliniumdiethylenetriaminepentaacetic acid in magnetic resonance imaging ofpatients treated by thrombolysis for acute myocardial infarction hasbeen reported (De Roos, A. et al., Int. J. Card. Imaging 7:133 (1991)).Radiolabeled and paramagnetically labeled alpha-ketoamide derivativeshave also been proposed as thrombus imaging agents (Abelman et al, U.S.Pat. No. 5,656,600).

[0011] Edwards et al., J. Amer. Chem. Soc. 114:1854-63(1992), describespeptidyl α-ketobenzoxazoles that reversibly inhibit the serine proteaseshuman leukocyte elastase and porcine pancreatic elastase.

[0012] European Published Application 363 284 describes analogs ofpeptidase substrates in which the nitrogen atom of the scissile amidegroup of the substrate peptide has been replaced by hydrogen or asubstituted carbonyl moiety.

[0013] Australian Published Application 86245677 also describespeptidase inhibitors having an activated electrophilic ketone moietysuch as fluoromethylene ketone or α-keto carboxyl derivatives.

[0014] Brown et al., J. Med. Chem. 37:1259-1261 (1994) describes orallyactive, non-peptidic inhibitors of human leukocyte elastase whichcontain trifluoromethylketone and pyridinone moieties.

[0015] H. Mack et al., J. Enzyme Inhibition, 9:73-86 (1995) describesrigid amidino-phenylalanine thrombin inhibitors which contain apyridinone moiety as a central core structure.

[0016] PCT International Published Application WO 97/01338 describespyridinone compounds having the formula:

[0017] where W is R¹, R¹OCO, R¹CO, R¹SO₂, or (R¹)_(m)(CH₂)_(n)NH_(q)CO;

[0018] R¹ is R²(CH₂)_(n), (R²)(OR²)CH(CH₂)_(p), (R²)₂CH(CH₂)_(n), andR²O(CH₂)_(p);

[0019] R² is hydrogen, optionally substituted phenyl, naphthyl,biphenyl, a mono- or bicyclic heterocyclic ring, COOR⁶, C₁₋₄ linear orbranched alkyl, C₃₋₇ cycloalkyl, or C₇₋₁₂ bicyclic alkyl;

[0020] R³ is hydrogen, C₁₋₄ linear or branched alkyl, C₃₋₇ cycloalkyl,or trifluoromethyl;

[0021] A is one of:

[0022] where Y is hydrogen, hydroxy, or CN; and

[0023] R⁶ is hydrogen, or C₁₋₄ linear or branched alkyl.

[0024] PCT International Published Application WO97/30708 disclosespyridinone compounds of the general formula:

[0025] The compounds are disclosed to be useful for inhibiting thrombinand associated thrombotic occlusions.

[0026] PCT Published Application WO 96/18644 describes compounds havingthe formula:

[0027] wherein

[0028] Het is selected from the group consisting of

[0029] and R₃ is selected from the group consisting of:

[0030] The compounds are described as specific inhibitors of thrombin.

[0031] A need continues to exist for non-peptidic compounds that arepotent and selective protease inhibitors, and which possess greaterbioavailability and fewer side-effects than currently available proteaseinhibitors. Accordingly, new classes of potent protease inhibitors,characterized by potent inhibitory capacity and low mammalian toxicity,are potentially valuable therapeutic agents for a variety of conditions,including treatment of a number of mammalian proteolytic disease states.

SUMMARY OF THE INVENTION

[0032] The present invention is directed to novel aminoguanidine andalkoxyguanidine compounds having Formula VII (below). Also provided areprocesses for preparing compounds of Formula VII. The novel compounds ofthe present invention are potent inhibitors of proteases, especiallytrypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin,plasmin and factor Xa. Certain of the compounds exhibit antithromboticactivity via direct, selective inhibition of thrombin, or areintermediates useful for forming compounds having antithromboticactivity. Also provided are methods of inhibiting or treating aberrantproteolysis in a mammal and methods of treating thrombosis, ischemia,stroke, restenosis or inflammation in a mammal by administering aneffective amount of a compound of Formula VII.

[0033] The invention includes a composition for inhibiting loss of bloodplatelets, inhibiting formation of blood platelet aggregates, inhibitingformation of fibrin, inhibiting thrombus formation, and inhibitingembolus formation in a mammal, comprising a compound of the invention ina pharmaceutically acceptable carrier. These compositions may optionallyinclude anticoagulants, antiplatelet agents, and thrombolytic agents.The compositions can be added to blood, blood products, or mammalianorgans in order to effect the desired inhibitions.

[0034] Also provided are methods of inhibiting or treating aberrantproteolysis in a mammal, and methods for treating myocardial infarction;unstable angina; stroke; restenosis; deep vein thrombosis; disseminatedintravascular coagulation caused by trauma, sepsis or tumor metastasis;hemodialysis; cardiopulmonary bypass surgery; adult respiratory distresssyndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis;induration; metastasis; hypercoagulability during chemotherapy;Alzheimer's disease; Down's syndrome; fibrin formation in the eye; andwound healing. Other uses of compounds of the invention are asanticoagulants either embedded in or physically linked to materials usedin the manufacture of devices used in blood collection, bloodcirculation, and blood storage, such as catheters, blood dialysismachines, blood collection syringes and tubes, blood lines and stents.

[0035] The invention also includes a method for reducing thethrombogenicity of a surface in a mammal by attaching to the surface,either covalently or noncovalently, a compound of the invention.

[0036] In another aspect, the present invention includes compositionswhich are useful for in vivo imaging of thrombi in a mammal, comprisinga compound of the present invention which is capable of being detectedoutside the body. Preferred are compositions comprising a compound ofthe present invention and a detectable label, such as a radioactive orparamagnetic atom.

[0037] In another aspect, the present invention provides diagnosticcompositions which are useful for in vivo imaging of thrombi in amammal, comprising a pharmaceutically acceptable carrier and adiagnostically effective amount of a compound or composition of thepresent invention.

[0038] In another aspect, the present invention includes methods whichare useful for in vivo imaging or thrombi in a mammal.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Compounds of the present invention include compounds of FormulaVII:

[0040] or a solvate, hydrate or pharmaceutically acceptable saltthereof; wherein:

[0041] R¹ is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl,aralkyl, heterocycle or heterocycloalkyl, any of which may be optionallysubstituted;

[0042] Z is —SO₂—, —OCO—, —CO—, —NR²CO— or a covalent bond,

[0043] where R² is hydrogen, alkyl, aralkyl, aryl, hydroxy(C₂₋₁₀)alkyl,amino(C₂₋₁₀)alkyl, monoalkylamino(C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkylor carboxyalkyl;

[0044] Het is selected from the group consisting of

[0045] where

[0046] R³, R⁴ and R⁵ are independently hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen,hydroxyalkyl, cyano, nitro, carboxamido, —CO₂R^(x), —CH₂OR^(x) or—OR^(x),

[0047] where R^(x), in each instance, is independently one of hydrogen,alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups mayoptionally have one or more unsaturations;

[0048] R⁶ is hydrogen, alkyl, aralkyl, aryl, cyano(C₂₋₁₀)alkyl,hydroxy(C₂₋₁₀)alkyl, alkoxy(C₂₋₁₀)alkyl, mono- anddi-alkylamino(C₂₋₁₀)alkyl, or carboxyalkyl;

[0049] R⁷ is hydrogen, C₁₋₄alkyl, or C₂₋₄alkenyl;

[0050] R⁸ is hydrogen, alkyl, alkenyl, aralkyl, aryl, hydroxyalkyl,aminoalkyl, monoalkylamino (C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl orcarboxyalkyl;

[0051] R¹², R¹³, R¹⁴ and R¹⁵ are independently hydrogen, alkyl, aralkyl,aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkylor carboxyalkyl;

[0052] or R¹² and R¹³ are taken together to form —(CH₂)_(y)—, where y is2 to 7, preferably 2 to 5, while R¹⁴ and R¹⁵ are defined as above;

[0053] or R¹⁴ and R¹⁵ are taken together to form —(CH₂)_(y)—, where q is2 to 7, preferably 2 to 5, while R¹² and R¹³ are defined as above;

[0054] or R¹² and R¹⁴ are taken together to form —(CH₂)_(r)—, where r is0 (a bond) or 1 to 7, preferably 0-4, while R¹³ and R¹⁵ are defined asabove;

[0055] X is oxygen or NR⁹,

[0056] where R⁹ is hydrogen, alkyl, cycloalkyl or aryl, wherein saidalkyl, cycloalkyl or aryl can be optionally substituted with amino,monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano ortrifluoromethyl;

[0057] R^(a), R^(b) and R^(c) are independently hydrogen, alkyl,hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or—CO₂R^(w), where

[0058] R^(w) is alkyl, cycloalkyl, phenyl, benzyl,

[0059] where R^(d) and R^(c) are independently hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl or phenyl, R^(f) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl orphenyl, R^(g) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or phenyl, and R^(h)is aralkyl or C₁₋₆alkyl;

[0060] n is from zero to 8; and

[0061] m is from zero to 6.

[0062] A preferred group of compounds falling within the scope of thepresent invention include compounds of Formula VII wherein R¹ is one ofC₆₋₁₀ ar(C₁₋₄) alkyl, C₆₋₁₀ aryl, C₄₋₇ cycloalkyl(C₁₋₄)alkyl,heterocycle or heterocyclo(C₁₋₄)alkyl wherein the heterocycle is a 5- to7-membered mono- or 9- to 10-membered bi-cyclic heterocyclic ring thatcan be saturated or unsaturated, which contains 1 to 3 heteroatomsselected from N, O and S. Any of these R¹ groups can be optionallysubstituted by 1-5, preferably by one, two or three of hydroxy, nitro,trifluoromethyl, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₆₋₁₀aryl, C₁₋₆alkoxy,C₆₋₁₀ar(C₁₋₆)alkoxy, C₁₋₆ aminoalkyl, C₁₋₆ aminoalkoxy, amino,mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl, carboxy, C₁₋₆ hydroxyalkyl,C₂₋₆ hydroxyalkoxy, (C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono- and di- C₁₋₄alkylamino (C₂₋₆)alkoxy, C₂₋₁₀ mono(carboxyalkyl)amino, bis(C₂₋₁₀carboxyalkyl) amino, C₆₋₁₄ ar(C₁₋₆) alkoxycarbonyl, C₂₋₆alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₂₋₆ alkenylsulfonyl, C₂₋₆alkynylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ ar(C₁₋₆) alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonamido, C₆₋₁₀ arylsulfonamido, C₆₋₁₀ar(C₁₋₆) alkylsulfonamido, amidino, guanidino, C₁₋₆ alkyliminoamino,formyliminoamino, C₂₋₆ carboxyalkoxy, C₂₋₆ carboxyalkyl,carboxyalkylamino, cyano, trifluoromethoxy, or perfluoroethoxy.

[0063] An especially preferred group of compounds include compounds ofFormula VII wherein R¹ is phenyl, benzyl, naphthyl, naphthylmethyl,pyridyl, pyridylmethyl, thienyl, thienylmethyl, quinolinyl orquinolinylmethyl, any of which is optionally substituted by one, two orthree optional substituents listed in the preceding paragraph,especially halo, such as chloro or fluoro, methoxy, methyl,trifluoromethyl, cyano, nitro, methylsulfonyl, amino or dimethylamino.

[0064] Useful values of R¹include, for example, benzyl, fluorobenzyl,chlorobenzyl, iodobenzyl, dichlorobenzyl, bromobenzyl,trifluoromethylbenzyl, methylsulfonylbenzyl, di(trifluoromethyl)benzyl,methylbenzyl, t-butylbenzyl, methoxybenzyl, dimethoxybenzyl,hydroxybenzyl, carboxybenzyl, aminobenzyl, methylaminobenzyl,n-butylaminobenzyl, amidinobenzyl, guanidinobenzyl,formyliminoaminobenzyl, acetimidoylaminobenzyl, methoxycarbonylbenzyl,ethoxycarbonylbenzyl, carboxymethoxybenzyl, naphthylmethyl,hydroxynaphthylmethyl, cyclohexylmethyl, cyclopentylmethyl, phenyl,chlorophenyl, iodophenyl, dichlorophenyl, bromophenyl,trifluoromethylphenyl, methylsulfonylphenyl, di(trifluoromethyl)phenyl,methylphenyl, t-butylphenyl, methoxyphenyl, dimethoxyphenyl,hydroxyphenyl, carboxyphenyl, aminophenyl, methylaminophenyl,n-butylaminophenyl, amidinophenyl, guanidinophenyl,formyliminoaminophenyl, acetimidoylaminophenyl, methoxycarbonylphenyl,ethoxycarbonylphenyl, carboxymethoxyphenyl, naphthyl, hydroxynaphthyl,cyclohexyl, and cyclopentyl. Additional useful values include pyridyl,thienyl, isoquinolinyl, pyridylmethyl, isoquinolinylmethyl,tetrahydroquinolinyl and tetrahydroquinolinylmethyl.

[0065] More preferred values of R¹ include phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl,4-methoxyphenyl, 4-methylphenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,5-dichlorophenyl,2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 2-methylsulfonylphenyl,4-isopropylphenyl, 3,4-dimethoxyphenyl, 2,4,6-trimethylphenyl,2,5-dimethylphenyl, 4-vinylphenyl, 2-chloro-6-methylphenyl,3-bromo-6-methoxyphenyl, 3-chloro-2-methylphenyl,2-chloro-5-trifluoromethylphenyl, 2,4-dichlorophenyl,2-butoxy-5-(1,1-dimethylpropyl)phenyl, 3-nitrophenyl,4-chloro-3-nitrophenyl, 4-methylcarbonylaminophenyl, 4-tert-butylphenyl,3-cyanophenyl, 4-methylsulfonylphenyl, pentafluorophenyl,2,5-dichlorophenyl, 2,4-dimethoxyphenyl, 2-methyl-5-nitrophenyl,3-chloro-2-cyanophenoxy)phenyl, 2-chloro-4-fluorophenyl,3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl, 4-phenylphenyl,2-propylbutyl, 5-chloro-2-methoxyphenyl, 2-cyanophenyl,2-(N-hydroxy)aminophenyl, 2-(4-biphenylmethoxy)phenyl,2-(3-biphenylmethoxy)phenyl, benzyl, 2-(phenylsulfonyl)phenyl,2,4-bis(methylsulfonyl)phenyl, 2-chloro-4-methylsulfonylphenyl, benzyl,3-chlorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl,2-iodobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 3-fluorobenzyl,4-chlorobenzyl, 2-chloro-6-fluorobenzyl, 2-fluorobenzyl,2,3-dichlorobenzyl, 3,4-difluorobenzyl, 2,4-dichlorobenzyl,2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2-methylbenzyl,5-chloro-2-methoxybenzyl, 2-cyanobenzyl, 2-(4-biphenylmethoxy)benzyl,2-(3-biphenylmethoxy)benzyl, 2-(phenylsulfonyl)benzyl,2,4-bis(methylsulfonyl)benzyl, 3-methylsulfonylbenzyl,2-chloro-4-methylsulfonylbenzyl, 1-naphthalenylmethyl,2-naphthalenylmethyl, and 2-naphthalenyl.

[0066] Additional preferred values of R¹ include dansyl, thien-2-yl,pyridin-2-yl, 3-methylquinolin-1-yl, 1-methylimidazol-4-yl,quinolin-5-yl, quinoline-8-yl, 6-bromonaphthalen-2-yl,6-chloronaphthalen-2-yl, 5-chlorothien-2-yl, 5-methyl-8-quinolinyl,8-quinolinylmethyl, 5-methyl-8-quinolinylmethyl,4-benzo-2,1,3-thiadiazolyl, and 5-chloro-1,3-dimethyl-4-pyrazolyl.

[0067] Preferred values of R² in Formula VII include hydrogen, C₁₋₆alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl, C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl, C₂₋₁₀aminoalkyl, C₂₋₇ carboxyalkyl, mono(C₁₋₄ alkyl)amino(C₁₋₈)alkyl, anddi(C₁₋₄ alkyl)amino(C₁₋₈)alkyl. Suitable values of R² include hydrogen,methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, 2-carboxymethyl,3-carboxyethyl, 4-carboxypropyl and 2-(dimethylamino)ethyl, withhydrogen being most preferred.

[0068] Preferred Het groups include

[0069] Preferred compounds are those where R³, R⁴ and Rs areindependently hydrogen, C₁₋₄ alkyl, C₃₋₇cycloalkyl, C₆₋₁₄aryl,especially C₆₋₁₀aryl, C₆₋₁₀ar(C₁₋₄)alkyl, trifluoromethyl, halogenhydroxyalkyl, cyano, nitro, carboxamide, carboxy, alkoxycarbonyl,carboxymethyl, alkoxycarbonylmethyl, or cycloalkyloxycarbonyl.

[0070] Useful values of R³, R⁴ and R⁵ include hydrogen, methyl, ethyl,propyl, chloro, bromo, trifluoromethyl, hydroxymethyl, methoxy, ethoxy,carboxamide, nitro, phenyl, cyclopropyl, hydroxy, isopropyl,methoxycarbonyl, ethoxycarbonyl and benzyl.

[0071] Preferred R³ and R⁴ groups include hydrogen, C₁₋₁₂ alkyl, andC₂₋₆ alkenyl. A most preferred value of R³ and R⁴ is hydrogen.

[0072] Preferred R⁵ groups include hydrogen, halogen, C₁₋₅alkyl,C₃₋₆alkenyl, C₃₋₅cycloalkyl, trifluoromethyl, and C₁₋₄alkoxy, morepreferably C₁₋₄alkyl, such as methyl, ethyl, propyl or isopropyl.

[0073] A particularly preferred Het, when R³ and R⁴ are independentlyselected to be hydrogen or methyl, is

[0074] wherein R⁵ is selected from the group consisting of hydrogen,methyl, ethyl, propenyl, allyl, propyl, isopropyl, butyl, R-sec-butyl,S-sec-butyl, isobutyl, 1-pentyl, R-2-pentyl, S-2-pentyl, 3-pentyl,S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl,R-1-(2-methyl)-butyl, cyclopentyl, 2-pyrolyl, 3-pyrolyl, 1-hexyl,S-2-hexyl, R-2-hexyl, R-3-hexyl, and S-3-hexyl. A particularly preferredHet according to this aspect has hydrogen, methyl, ethyl, propyl orisopropyl as R⁵.

[0075] Preferred values of Z include —SO₂— and a covalent bond.

[0076] A preferred R⁷ group is hydrogen.

[0077] Preferred compounds are those of Formula VII, where R⁸ ishydrogen, C₁₋₆alkyl or C₆₋₁₀ aryl (C₁₋₆)alkyl.

[0078] Preferred compounds when X is NR⁹ are those wherein R⁹ ishydrogen or C₁₋₆ alkyl, optionally substituted by one, two or three,preferably one, of amino, monoalkylamino, dialkylamino, alkoxy, hydroxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboalkoxy, phenyl,cyano, trifluoromethyl, acetylamino, pyridyl, thiophenyl, furyl,pyrrolyl or imidazolyl.

[0079] Suitable values of R⁹ include hydrogen, methyl, ethyl, propyl,n-butyl, benzyl, phenethyl, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, carboxymethyl and carboxyethyl.

[0080] Most preferred compounds are those where X is oxygen.

[0081] Preferred compounds are those of Formula VII, where R¹², R¹³, R¹⁴and R¹⁵ are independently one of hydrogen, C₁₋₆alkyl,C₆₋₁₀ar(C₁₋₆)alkyl, C₆₋₁₀ aryl, C₂₋₁₀hydroxyalkyl or C₂₋₇ carboxyalkyl.Useful values of R¹², R¹³, R¹⁴ and R¹⁵ include hydrogen, methyl, ethyl,propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, 2-carboxymethyl, 3-carboxyethyl and 4-carboxypropyl.Additional preferred compounds are those where R¹² and R¹³ are takentogether to form —(CH₂)_(y)— where y is 2.

[0082] Preferred values of R^(a), R^(b) and R^(c) in Formula VII areindependently hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, cyano or—CO₂R^(w), where R^(w), in each instance, is preferably one ofC₁₋₄alkyl, C₄₋₇cycloalkyl or benzyloxycarbonyl. Suitable values ofR^(a), R^(b) and R^(c) include hydrogen, methyl, ethyl, propyl, n-butyl,hydroxy, methoxy, ethoxy, cyano, —CO₂CH₃, —CO₂CH₂CH₃ and —CO₂CH₂CH₂CH₃.In the most preferred embodiments, R^(a), R^(b) and R^(c) are eachhydrogen.

[0083] Also preferred at R^(a), R^(b) and R^(c) is the group —CO₂R^(w),where R^(w) is one of

[0084] where R^(d)-R^(h) are defined as above. When R^(a), R^(b) andR^(c) are —CO₂R^(w), where R^(w) is one of one of these moieties, theresulting compounds are prodrugs that possess desirable formulation andbioavailability characteristics. A preferred value for each of R^(d),R^(e) and R^(g) is hydrogen, R^(f) is methyl, and preferred values forR^(h) include benzyl and tert-butyl.

[0085] Preferred values of n in Formula VII include from zero to 6. morepreferably from zero to 4, and most preferably zero, 1 or 2.

[0086] Preferred values of m are from zero to 4, most preferably zero, 1or 2.

[0087] In the most preferred compounds m and n are both zero.

[0088] According to a particularly preferred aspect, provided arecompounds of Formula VII wherein Z is —SO₂—, R¹ is substituted orunsubstituted aryl or aralkyl, Het is

[0089] X is O, R⁸ is hydrogen, C₁₋₆ alkyl or C₆₋₁₀ aryl (C₁₋₆)alkyl andR^(a), R^(b) and R^(c) are all hydrogen. A very preferred aspect isdirected to such compounds where R¹ is substituted or unsubstitutedbenzyl or phenyl, X is O, and R⁸ is hydrogen, C₁₋₆alkyl, or C₆₋₁₀aryl(C₁₋₆)alkyl, and R^(a), R^(b) and R^(c) are all hydrogen.

[0090] A preferred group of compounds has Formula VIII:

[0091] or a solvate, hydrate of pharmaceutically acceptable saltthereof; wherein

[0092] Z′ is —OCO—, —CO—, —SO₂—, —NHCO—, or a covalent bond;

[0093] R²¹ is R²²(CH₂)_(k), where k is 0-4, (R²²)(OR²²)CH(CH₂)_(p),where p is 1-4, (R²²)₂CH(CH₂)_(k), where k is 0-4 and R²² can be thesame or different, and wherein (R²²)₂ can also be a ring substituent onCH represented by C₃₋₇ cycloalkyl, C₇₋₁₂ bicyclic alkyl, or a 5- to7-membered mono-, or 9- to 10-membered bicyclic heterocyclic ring whichcan be saturated or unsaturated, and which contains from one to threeheteroatoms selected from the group consisting of N, O and S, andR²²O(CH₂)_(p), wherein p is 1-4;

[0094] R²² is hydrogen; phenyl, unsubstituted or substituted with one ormore of C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, trifluoromethyl, hydroxy, COOH,or CONH₂; naphthyl; biphenyl; a 5- to 7-membered mono- or a 9- to10-membered bicyclic heterocyclic ring which can be saturated or

[0095] where R^(d) and R^(c) are independently hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl or phenyl, R^(f) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl orphenyl, R^(g) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or phenyl, and R^(h)is aralkyl or C₂₋₁₀alkyl;

[0096] R³², R³³, R³⁴ and R³⁵ are independently one of hydrogen,C₁₋₆alkyl, C₂₋₁₀ carboxyalkyl or C₂₋₁₀hydroxyalkyl, or R³² and R³³ aretaken together to form —(CH₂)_(y)—, where y is 2 to 5, while R³⁴ and R³⁵are defined as above; or R³⁴ and R³⁵ are taken together to form—(CH₂)_(q)—, where q is 2 to 5, while R³² and R³³ are defined as above;or R³² and R³⁴ are taken together to form —(CH₂)_(r)—, where r is 0 (abond) or 1-4, while R³³ and R³⁵ are defined as above;

[0097] R²⁸ is hydrogen, C₁₋₄alkyl or C₆₋₁₀aryl(C₁₋₄)alkyl; X′ is O;

[0098] n is from zero to 4; and

[0099] m is zero to 2.

[0100] A useful class of compounds is the embodiment wherein Z′ is acovalent bond or —SO₂—. A further useful subclass of compounds is theembodiment wherein R²¹ is R²²(CH₂)_(k), (R²²)₂CH(CH₂)_(k), phenyl, or(phenyl)₂—CH.

[0101] Another useful class of compounds is the embodiment wherein R²⁵is C₁₋₄ alkyl and particularly wherein R²⁵ is methyl, ethyl, propyl orisopropyl.

[0102] Another useful class of compounds it's the embodiment wherein R²⁸is hydrogen or C₁₋₄ alkyl, and X′ is O.

[0103] Exemplary structures of compounds within the scope of theinvention include the following:

[0104] as well as pharmaceutically acceptable salts thereof, for examplethe hydrochloride and acetate salts thereof.

[0105] Examples of novel individual compounds falling within the scopeof the present invention include:

[0106]3-Benzylsulfonylamino-6-methyl-1-[(3-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0107]3-Benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0108]3-Benylsulfonylamino-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0109]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0110]3-(Benzyloxycarbonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0111]3-(Benzylsulfonyl)amino-6-methyl-1-[(1-(1-guanidinooxymethyl)cyclopropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0112]3-(Benzylsulfonyl)amino-6-methyl-1-[(4-guanidinooxy)piperidinylcarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0113]3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0114]3-(3-Trifluoromethylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0115]3-(2-Trifluoromethylbenzyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0116]3-(2-Iodobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0117]3-(2-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0118]3-(2-Bromobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0119]3-(3-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0120]3-(4-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0121]3-((2-Chloro-6-fluoro)benzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0122]3-(2-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0123]3-(2,3-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0124]3-(3,4-Difluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0125]3-(2,4-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0126]3-(2,5-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0127]3-(3,4-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0128]3-(1-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0129]3-(2-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0130]3-(2-Methylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0131]3-(3-Chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0132]3-(3,4-Dichlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0133]3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0134]3-(4-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0135]3-(Phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0136]3-(3-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0137]3-(2-Methylsulfonylphenyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0138]3-(2-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0139]3-(4-Bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0140]3-(4-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0141]3-(4-Iodophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0142]3-(4-Methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0143]3-(4-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0144]3-(3-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0145]3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0146]3-(3-Chloro-4-fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0147]3-(4-Isopropylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0148]3-(3-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0149]3-(3,5-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0150]3-(3,4-Dimethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0151]3-(2-Thienylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0152]3-(1-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;3-(2,4,6-Trimethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmpethyl]-2-pyridinonetrifluoroacetate;

[0153]3-(2-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0154]3-(2,5-Dimethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0155]3-(2-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0156]3-(2-Chloro-6-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0157]3-(3-Bromo-6-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0158]3-(3-Chloro-2-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0159]3-(2-Chloro-5-trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0160]3-(2,4-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0161]3-(4-Vinylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0162]3-(2-Butoxy-5-(1,1-dimethylpropyl)phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate;

[0163]3-(3-Nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0164]3-(4-Chloro-3-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0165]3-(4-Methylcarbonylaminophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0166]3-(4-tert-Butylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0167]3-(4-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0168]3-(3-Cyanophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0169]3-(4-Methylsulfonylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0170]3-Dansylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0171]3-(Pentafluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0172]3-(2,5-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0173]3-(2-Nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0174]3-Di(4-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0175]3-(2,5-Dimethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0176]3-(4-Propylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0177]3-(2-Methyl-5-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0178]3-(2-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0179]3-(2,3-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0180]3-(2-Trifluoromethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0181]3-(4-(3-Chloro-2-cyanophenoxy)phenylsulfonyl)amino-6-methyl-1-[(2-guanidino-oxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate;

[0182]3-(2-Chloro-4-fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0183]3-(3-Chloro-6-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0184]3-(2-Methoxy-5-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0185]3-(4-Phenylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0186]3-(5-Chlorothiophene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0187]3-(6-Chloronaphthalene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0188]3-(6-Bromonaphthalene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0189]3-(3-Bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0190]3-(Quinoline-8-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonyImethyl]-2-pyridinonetrifluoroacetate;

[0191]3-(Quinoline-5-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0192]3-(1-Methylimidazole-4-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0193] 3-(3-Methylquinoline-8-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0194]3-(2-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0195]3-(3-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0196]3-(4-Ethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonyImethyl]-2-pyridinonetrifluoroacetate;

[0197]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)-N-methylaminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0198]3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0199]3-(3-Methylphenylsulfonyl)amino-6-ethyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0200]3-(3-Methylphenylsulfonyl)amino-6-propyl-1-{2-(guanidinyloxyethyl)aminocabonylmethyl}-2-pyridinonetrifluoroacetate;

[0201]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride;

[0202]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-ethylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride;

[0203]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-benzylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride;

[0204]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-butylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride;

[0205] 3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0206]3-(Benzylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

[0207]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N-methoxycarbonyl)guanidino-oxyethyl)aminocarbonylmethyl]-2-pyridinone;

[0208]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N′,N″-triethoxycarbonyl)guanidino-oxyethyl)aminocarbonylmethyl]-2-pyridinone;

[0209]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N′-diethoxycarbonyl)guanidino-oxyethyl)aminocarbonylmethyl]-2-pyridinone;and

[0210]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N-ethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone.

[0211] It is also to be understood that the present invention isconsidered to include stereoisomers as well as optical isomers, e.g.mixtures of enantiomers as well as individual enantiomers anddiastereomers, which arise as a consequence of structural asymmetry inselected compounds of the present series.

[0212] The compounds of Formula VII may also be solvated, especiallyhydrated. Hydration may occur during manufacturing of the compounds orcompositions comprising the compounds, or the hydration may occur overtime due to the hygroscopic nature of the compounds.

[0213] Certain compounds within the scope of Formula VII are derivativesreferred to as prodrugs. The expression “prodrug” denotes a derivativeof a known direct acting drug, which derivative has enhanced deliverycharacteristics and therapeutic value as compared to the drug, and istransformed into the active drug by an enzymatic or chemical process.Useful prodrugs are those where R^(a), R^(b) and/or R^(c) are CO₂R^(w),where R^(w) is defined above. See, U.S. Pat. No. 5,466,811 and Saulnieret al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).

[0214] When any variable occurs more than one time in any constituent orin Formula VII, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

[0215] In another aspect, the present invention includes compositionswhich are useful for in vivo imaging of thrombi in a mammal, comprisinga compound of the present invention which is capable of being detectedoutside the body. Preferred are compositions comprising a compound ofthe present invention and a detectable label, such as a radioactive orparamagnetic atom.

[0216] In another aspect, the present invention includes methods whichare useful for in vivo imaging or thrombi in a mammal.

[0217] According to a preferred aspect, useful compounds are thosewherein the R¹ substituent is substituted with a detectable label, suchas a radioactive iodine atom, such as I-125, I-131 or I-123. In thisaspect, R¹ is preferably phenyl, having a para I-123, para I-125 or paraI-131 substitution, or benzyl, having a meta I-123, meta I-125 or metaI-131 substitution.

[0218] The detectable label can also be a radioactive or paramagneticchelate in which a suitable ligand (L) is attached to an R¹ substituent,either directly or via a divalent linking group A″. Alternatively, thegroup —A″-L substitutes for the groups -Z-R¹ in Formula VII. By suitableligand is meant an organic moiety that is capable of chelating aradioactive or paramagnetic metal ion.

[0219] In these compounds, the divalent linking group A″ includes groupsthat are capable of covalently bonding with a free amino group and thechelating means. For example, A″ may be —C(═S)—, —C(═O)—,—C(═NH)—(CH₂)₆—C(═NH)—, —C(═O)—(CH₂)₆—C(═O)—,

[0220] and the like.

[0221] Also, in the compounds represented by Formula VII, the chelatingligand, L, includes groups capable of covalently bonding to ornoncovalently binding to either a radioactive or paramagnetic atom. Thechelating means including those which are customarily used forcomplexing radioactive or paramagnetic atoms. These include chelatingmeans containing 3 to 12, preferably 3 to 8, methylene phosphonic acidgroups, methylene carbohydroxamic acid groups, carboxyethylidene groups,or especially carboxymethylene groups, which are bonded to a nitrogenatom. If only one or two of the acid groups are bonded to a nitrogenatom, then that nitrogen is bonded to another nitrogen atom having suchgroups by an optionally substituted ethylene groups or by up to fourseparated ethylene units separated by a nitrogen or oxygen or sulfuratom. Preferred as a completing means isdiethylenetrimine-N,N,N′,N″,N″-pentaacetic acid (DTPA). DTPA is wellknown in the art as a chelating means for the radioactive atomindium-111 (In-111), technetium-99m (Tc-99m), and the paramagnetic atomgadolinium (Gd). Khaw, et al., Science 209:295 (1980); Paik C. H. etal., U.S. Pat. No. 4,652,440 (1987); Gries, H. et al., U.S. Pat. No.4,957,939 (1990). A preferred chelating ligand, L, is1-(p-aminobenzyl)-diethylenetriarninepentaacetic acid. Also included aschelating means are compounds which contain sulfhydryl or aminemoieties, the total of which in any combination is at least four. Thesesulfhydryl or amine moieties are separated from each other by at leasttwo atoms which can be either carbon, nitrogen, oxygen, or sulfur.Especially preferred for chelating means, L, is metallothionein which iswell known in the art as a chelating means for Tc-99m.

[0222] The term “alkyl” as employed herein by itself or as part ofanother group refers to both straight and branched chain radicals of upto 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.

[0223] The term “alkenyl” is used herein to mean a straight or branchedchain radical of 2-20 carbon atoms, unless the chain length is limitedthereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, thealkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8carbon atoms in length most preferably from 2 to 4 carbon atoms inlength.

[0224] The term “alkynyl” is used herein to mean a straight or branchedchain radical of 2-20 carbon atoms, unless the chain length is limitedthereto, wherein there is at least one triple bond between two of thecarbon atoms in the chain, including, but not limited to, acetylene,1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms inlength, most preferably from 2 to 4 carbon atoms in length.

[0225] In all instances herein where there is an alkenyl or alkynylmoiety as a substituent group, the unsaturated linkage, i.e., thevinylene or acetylene linkage is preferably not directly attached to anitrogen, oxygen or sulfur moiety.

[0226] The term “alkoxy” is used herein to mean a straight or branchedchain radical of 1 to 20 carbon atoms, unless the chain length islimited thereto, bonded to an oxygen atom, including, but not limitedto, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably thealkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8carbon atoms in length.

[0227] The term “aryl” as employed herein by itself or as part ofanother group refers to monocyclic or bicyclic aromatic groupscontaining from 6 to 12 carbons in the ring portion, preferably 6-10carbons in the ring portion, such as phenyl, naphthyl ortetrahydronaphthyl.

[0228] The term “heteroaryl” as employed herein refers to groups having5 to 14 ring atoms; 6, 10 or 14 π electrons shared in a cyclic array;and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroatoms (where examples of heteroaryl groups are: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,4αH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl and phenoxazinyl groups).

[0229] The term “aralkyl” or “arylalkyl” as employed herein by itself oras part of another group refers to C₁₋₆alkyl groups as discussed abovehaving an aryl substituent, such as benzyl, phenylethyl or2-naphthylmethyl.

[0230] The term “cycloalkyl” as employed herein by itself or as part ofanother group refers to cycloalkyl groups containing 3 to 9 carbonatoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.

[0231] The term “C₇₋₁₂bicyclic alkyl” is intended to includebicyclo[2.2.1]heptyl (norbornyl), bicyclo[2.2.2]octyl,1,1,3-trimethylbicyclo[2.2.1]heptyl (bornyl), and the like.

[0232] The terms “alkoxy” refers to any of the above alkyl groups linkedto an oxygen atom.

[0233] The term “halogen” or “halo” as employed herein by itself or aspart of another group refers to chlorine, bromine, fluorine or iodinewith chlorine being preferred.

[0234] The term “monoalkylamine” as employed herein by itself or as partof another group refers to an amino group which is substituted with onealkyl group having from 1 to 6 carbon atoms.

[0235] The term “dialkylamine” as employed herein by itself or as partof another group refers to an amino group which is substituted with twoalkyl groups, each having from 1 to 6 carbon atoms.

[0236] The term “hydroxyalkyl” as employed herein refers to any of theabove alkyl groups substituted by one or more hydroxyl moieties.

[0237] The term “carboxyalkyl” as employed herein refers to any of theabove alkyl groups substituted by one or more carboxylic acid moieties.

[0238] The term “heterocycle” or “heterocyclic ring”, as used hereinexcept where noted, represents a stable 5- to 7-membered mono- orbicyclic or stable 7- to 10-membered bicyclic heterocyclic ring systemany ring of which may be saturated or unsaturated, and which consists ofcarbon atoms and from one to three heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring.Especially useful are rings containing one oxygen or sulfur, one tothree nitrogen atoms, or one oxygen or sulfur combined with one or twonitrogen atoms. The heterocyclic ring may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.Examples of such heterocyclic groups include piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, andoxadiazolyl. Morpholino is the same as morpholinyl.

[0239] The term “heteroatom” is used herein to mean an oxygen atom(“O”), a sulfur atom (“S”) or a nitrogen atom (“N”). It will berecognized that when the heteroatom is nitrogen, it may form anNR^(a)R^(b) moiety, wherein R^(a) and R^(b) are, independently from oneanother, hydrogen or C₁ to C₈ alkyl, or together with the nitrogen towhich they are bound, form a saturated or unsaturated 5-, 6-, or7-membered ring.

[0240] Schemes 1 and 2 outline the synthesis of compounds of the presentinvention where R¹—Z— is R¹—SO₂—.

[0241] where R¹²-R¹⁵, R^(a), R^(b), R^(c), n and m are as defined above.

[0242] In Scheme 1, an aminoalcohol 1 is protected using a standardamino protecting group such as benzyloxycarbonyl (Cbz) to give compound2. The protected aminoalcohol 2 is coupled to N-hydroxyphthalimide usinga Mitsunobu coupling procedure (Mitsunobu, O., Synthesis, 1 (1981)) toprovide compound 3. Preferred coupling conditions include using asolvent, such as tetrahydrofuran or methylene chloride, and a dialkylazodicarboxylate, such as diethyl azodicarboxylate. Unveiling of thephthalimide protecting group to form alkoxyamine 4 is accomplished usingstandard conditions well known in the art (Greene, T. W., Wuts, P. G.W., Protecting Groups in Organic Synthesis, 2nd edition, John Wiley andSons, Inc. New York, (1991)), such as methylamine or hydrazine, in anappropriate solvent, such as ethanol or iso-propanol. Guanidinylation ofthe resulting alkoxyamine 4 to 5 is accomplished using substitutedguanidinylating reagents such asN,N′-bis(tert-butoxycarbonyl)-S-methylthiourea (Bergeron, R. J. andMcManis, J. S, J. Org. Chem., 52:1700 (1987)) or N—R^(a), N—R^(b),N—R^(c)-1H-pyrazole-1-carboxamidine (Bernatowicz, M. S., et al.,Tetrahedron Letter 34: 3389 (1993)). Deprotection of the aminoprotecting group to give intermediates 6 is accomplished using standardprocedures well known in the art (Greene, T. W., Wuts, P. G. W.,Protecting Groups in Organic Synthesis, 2nd edition, John Wiley andSons, Inc. New York, (1991)), such as palladium on carbon, in a suitablesolvent, such as chloroform in methanol or ethanol. In some cases, it isadvantageous to add an acid, such as hydrochloric acid.

[0243] where R¹, R³-R⁵, R¹²-R¹⁵, R⁸, R^(a), R^(b), R^(c), n and m aredefined above.

[0244] In Scheme 2, a 2-hydroxy-pyridine carboxylic acid 7 is reactedwith diphenylphosphoryl azide (DPPA), triethylamine and benzyl alcoholin a suitable solvent, such as dioxane to afford the protected aminopyridinone 8. This is alkylated with a glycine equivalent, such astert-butyl bromoacete, using a base, such as lithiumhexamethyldisilazide, cesium carbonate, or sodium hydride, in anappropriate solvent, such as tetrahydrofuran or N,N-dimethylformamide togive compound 9. The tert-butyl group is then removed using standardconditions well known in the art (Greene, T. W., Wuts, P. G. W.,Protecting Groups in Organic Synthesis, 2nd edition, John Wiley andSons, Inc. New York, (1991)), such as HCl gas in ethyl acetate ortrifluoroacetic acid in methylene chloride, to afford acid 10. The acid10 is coupled to intermediate 6 using a standard peptide couplingreagents, such as Castro's reagent (BOP) or PyBOP, and base such asdiisopropylethylamine in a suitable solvent, such asN,N-dimethylformamide to produce compound 14. The Cbz group is removedvia hydrogenation over a catalyst such as palladium on carbon in asolvent, such as tetrahydofuran and ethanol. The amine 15 is treatedwith a sulfonyl chloride in the present of a base, such as4-methylmorpholine, in a suitable solvent, such as methylene chloride toafford compound 16.

[0245] Alternatively, the Cbz group of compound 9 is deprotected using astandard procedure such as hydrogenation in the present of a catalystsuch as palladium on carbon in an appropriate solvent, such astetrahydrofuran and ethanol. The amine 11 is reacted with a sulfonylchloride in the present of a base, such as 4-methylmorpholine, in asuitable solvent, such as methylene chloride to afford 12. Thetert-butyl group is removed using standard procedure well known in theart (Greene, T. W., Wuts, P. G .W., Protecting Groups in OrganicSynthesis, 2nd edition, John Wiley and Sons, Inc. New York, (1991)),such as HCl gas in ethyl acetate or trifluoroacetic acid in methylenechloride, to afford acid 13. The acid 13 is coupled to intermediate 6using a standard peptide coupling reagents, such as Castro's reagent(BOP) or PyBOP, and a base such as diiso-propylethylamine, in a suitablesolvent, such as N,N-dimethylformamide to give compound 16. The R^(a),R^(b) and R^(c) can be optionally removed using a standard procedure. Inthe case of R^(a) and R^(b)=tert-butoxycarbonyl (Boc) andR^(c)=hydrogen, the Boc groups can be removed by treatment with an acid,such as trifluoroacetic acid or hydrochloric acid, in an appropriatesolvent, such as methylene chloride or dioxane to provide compound 17.Compound 17 can be then optionally alkylated with an alkyl halide in thepresent of a base, such as sodium bicarbonate, in an appropriatesolvent, such as N,N′-dimethylformamide, to give compound 18.

[0246] where R³, R⁵, R¹²-R¹⁵, R^(a), R^(b), R^(c), n, and m are definedabove, and Ar is aryl.

[0247] In Scheme 3, diethyl ethoxymethylenemalonate 19 is treated withamidine 20 in the present of base, such as sodium ethoxide, in anappropriate solvent, such as ethanol to afford substituted pyrimidine21. Compound 21 is alkylated with a glycine equivalent, such astert-butyl bromoacetate, using a base, such as tetrabutylammoniumfluoride, lithium hexamethyldisilazide, or sodium hydride, in anappropriate solvent, such as tetrahydrofuran or N,N-dimethylformamide togive ester 22. The ester is hydrolyzed with lithium hydroxide or sodiumhydroxide in a suitable solvent, such as methanol or ethanol, to affordacid 23. The acid is then treated with diphenylphosphoryl azide (DPPA)in the present of base, such as triethylamine, to form the acyl azidewhich undergoes the Curtius rearrangement reaction with benzyl alcoholto form the benzyloxycarbonyl (Cbz) protected 5-aminopyrimidione 24. TheCbz group of compound 24 is deprotected using a standard procedure suchas hydrogenation in the present of a catalyst, such as palladium oncarbon in an appropriate solvent, such as tetrahydrofuran and ethanol.The amine 25 is treated with a sulfonyl chloride in the present of abase, such as 4-methylmorpholine or triethylamine, in a suitablesolvent, such as methylene chloride to afford 26. The tert-butyl groupis removed using a standard procedure well known in the art (Greene, T.W., Wuts, P. G. W., Protecting Groups in Organic Synthesis, 2nd edition,John Wiley and Sons, Inc. New York, (1991)), such as trifluoroaceticacid in methylene chloride, to afford acid 27. The acid 27 is coupled tointermediate 6 using standard peptide coupling reagents, such asCastro's reagent (BOP) or PyBOP, and a base, such asdiiso-propylethylamine or triethylamine, in a suitable solvent, such asN,N-dimethylformamide to give compound 28. The R^(a), R^(b) and R^(c)can be optionally removed using a standard procedure. In the case ofR^(a) and R^(b)=tert-butoxycarbonyl (Boc) and R^(c)=hydrogen, the Bocgroups can be removed by treatment with an acid, such as trifluoroaceticacid or hydrochloric acid, in an appropriate solvent, such as methylenechloride or dioxane to provide compound 29. Compound 29 can beoptionally alkylated with an alkyl halide in the present of a base, suchas sodium bicarbonate, in a suitable solvent, such asN,N-dimethylformamide, to give compound 30.

[0248] Scheme 4 illustrates the preparation of compounds of the presentinvention where Z═—OCO—, —CO— or —NR²CO—. The amine 11 is reacted withan alkoxy carbonyl chloride, or a aryloxy carbonyl chloride, or a acylchloride in the present of a base, such as 4-methylmorpholine ortriethylamine, in a suitable solvent, such as methylene chloride, ortreated with a isocyanate in an appropriate solvent, such as methylenechloride or toluene, to afford 31. The tert-butyl group is removed usingstandard procedures well known in the art (Greene, T. W., Wuts, P. G.W., Protecting Groups in Organic Synthesis, 2nd edition, John Wiley andSons, Inc. New York, (1991)), such as HCl gas in ethyl acetate ortrifluoroacetic acid in methylene chloride, to afford acid 32. The acid32 is coupled to intermediate 6 using a standard peptide couplingreagent, such as Castro's reagent (BOP) or PyBOP, and a base such asdiisopropylethylamine, in a suitable solvent, such asN,N-dimethylformamide, to give compound 33. Alternatively, the amine 15is treated with an alkoxy carbonyl chloride, aryloxy carbonyl chlorideor acyl chloride in the present of a base, such as 4-methylmorpholine ortriethylemine, in a suitable solvent, such as methylene chloride, ortreated with a isocyanate in an appropriate solvent, such as methylenechloride or toluene, to afford compound 33. The R^(a), R^(b) and R^(c)can be optionally removed using a standard procedure. In the case ofR^(a) and R^(b)=tert-butoxycarbonyl (Boc) and R^(c)=hydrogen, the Bocgroups can be removed by treatment with an acid, such as trifluoroaceticacid or hydrochloric acid, in an appropriate solvent, such as methylenechloride or dioxane, to provide compound 34. The compound 34 can be thenoptionally alkylated with an alkyl halide in the present of a base, suchas sodium bicarbonate, in an appropriate solvent, such asN,N-dimethylformamide, to give compound 35.

[0249] Schemes 5 and 6 provide examples of intermediates and syntheticsteps described in Schemes 1 and 2 to produce compounds of Formula VIIwhere R¹—Z is R¹—SO₂—. The variable “m” in the schemes has a value offrom 0 to 8, preferably 0 or 1. The synthetic steps in these schemes areexemplified in Examples 1 and 2 herein.

[0250] The pharmaceutically-acceptable salts of the compounds of FormulaVII (in the form of water- or oil-soluble or dispersible products)include the conventional non-toxic salts or the quaternary ammoniumsalts which are formed, e.g., from inorganic or organic acids or bases.Examples of such acid addition salts include acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, andundecanoate. Base salts include ammonium salts, alkali metal salts suchas sodium and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others. Preferred acids for forming acidaddition salts include HCl and acetic acid.

[0251] The compounds of the present invention represent a novel class ofpotent inhibitors of metallo, acid, thiol and serine proteases. Examplesof the serine proteases inhibited by compounds within the scope of theinvention include leukocyte neutrophil elastase, a proteolytic enzymeimplicated in the pathogenesis of emphysema; chymotrypsin and trypsin,digestive enzymes; pancreatic elastase, and cathepsin G, achymotrypsin-like protease also associated with leukocytes; thrombin andfactor Xa, proteolytic enzymes in the blood coagulation pathway.Inhibition of thermolysin, a metalloprotease, and pepsin, an acidprotease, are also contemplated uses of compounds of the presentinvention. The compounds of the present invention are preferablyemployed to inhibit trypsin-like proteases.

[0252] An end use application of the compounds that inhibit chymotrypsinand trypsin is in the treatment of pancreatitis. For their end-useapplication, the potency and other biochemical parameters of theenzyme-inhibiting characteristics of the compounds of the presentinvention is readily ascertained by standard biochemical techniques wellknown in the art. Actual dose ranges for their specific end-useapplication will, of course, depend upon the nature and severity of thedisease state of the patient or animal to be treated, as determined bythe attending diagnostician. It is expected that a useful dose rangewill be about 0.01 to 10 mg per kg per day for an effective therapeuticeffect.

[0253] Compounds of the present invention that are distinguished bytheir ability to inhibit thrombin may be employed for a number oftherapeutic purposes. As thrombin inhibitors, compounds of the presentinvention inhibit thrombin production. Therefore, these compounds areuseful for the treatment or prophylaxis of states characterized byabnormal venous or arterial thrombosis involving either thrombinproduction or action. These states include, but are not limited to, deepvein thrombosis; disseminated intravascular coagulopathy which occursduring septic shock, viral infections and cancer; myocardial infarction;stroke; coronary artery bypass; fibrin formation in the eye; hipreplacement; and thrombus formation resulting from either thrombolytictherapy or percutaneous transluminal coronary angioplasty (PCTA). Otheruses include the use of said thrombin inhibitors as anticoagulantseither embedded in or physically linked to materials used in themanufacture of devices used in blood collection, blood circulation, andblood storage, such as catheters, blood dialysis machines, bloodcollection syringes and tubes, and blood lines. The compounds of thepresent invention may also be used as an anticoagulant in extracorporealblood circuits.

[0254] Metal stents have been shown to reduce restenosis, but arethrombogenic. A strategy for reducing the thrombogenicity of stents isto coat, embed, adsord or covalently attach a thrombin-inhibiting agentto the stent surface. The compounds of the present invention can beemployed for this purpose. Compounds of the invention can be attachedto, or embedded within soluble and/or biodegradeable polymers as andthereafter coated onto stent materials. Such polymers can includepolyvinylpyrrolidone, polyhydroxy-propylmethacrylamide-phenol,polyhydroxyethyl -aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues, polylactic acid, polyglycolic acid,copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels. See European Application 761 251,European Application 604,022, Canadian Patent 2,164,684 and PCTPublished Applications WO 96/11668, WO 96/32143 and WO 96/38136.

[0255] By virtue of the effects of thrombin on a host of cell types,such as smooth muscle cells, endothelial cells and neutrophils, thecompounds of the present invention find additional use in the treatmentor prophylaxis of adult respiratory distress syndrome; inflammatoryresponses; wound healing; reperfusion damage; atherosclerosis; andrestenosis following an injury such as balloon angioplasty, atherectomy,and arterial stent placement.

[0256] The compounds of the present invention may be useful in treatingneoplasia and metastasis as well as neurodegenerative diseases, such asAlzheimer's disease and Parkinson's disease.

[0257] When employed as thrombin inhibitors, the compounds of thepresent invention may be administered in an effective amount within thedosage range of about 0.1 to about 500 mg/kg, preferably between 0.1 to10 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.

[0258] When employed as inhibitors of thrombin, the compounds of thepresent invention may be used in combination with thrombolytic agentssuch as tissue plasminogen activator, streptokinase, and urokinase.Additionally, the compounds of the present invention may be used incombination with other antithrombotic or anticoagulant drugs such as,but not limited to, fibrinogen antagonists and thromboxane receptorantagonists.

[0259] The thrombin inhibitors may also be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propylmethacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the thrombininhibitors may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross linked oramphipathic block copolymers of hydrogels.

[0260] Human leucocyte elastase is released by polymorphonuclearleukocytes at sites of inflammation and thus is a contributing cause fora number of disease states. Compounds of the present invention areexpected to have an anti-inflammatory effect useful in the treatment ofgout, rheumatoid arthritis and other inflammatory diseases, and in thetreatment of emphysema. The leucocyte elastase inhibitory properties ofcompounds of the present invention are determined by the methoddescribed below. Cathepsin G has also been implicated in the diseasestates of arthritis, gout and emphysema, and in addition,glomerulonephritis and lung infestations caused by infections in thelung. In their end-use application the enzyme inhibitory properties ofthe compounds of Formula I is readily ascertained by standardbiochemical techniques that are well-known in the art.

[0261] The Cathepsin G inhibitory properties of compounds within thescope of the present invention are determined by the following method. Apreparation of partially purified human Cathepsin G is obtained by theprocedure of Baugh et al., Biochemistry 15:836 (1979). Leukocytegranules are a major source for the preparation of leukocyte elastaseand cathepsin G (chymotrypsin-like activity). Leukocytes are lysed andgranules are isolated. The leukocyte granules are extracted with 0.20 Msodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Trisbuffer, pH 8.0 containing 0.05 M NaCl overnight at 4° C. A proteinfraction precipitates during dialysis and is isolated by centrifugation.This fraction contains most of the chymotrypsin-like activity ofleukocyte granules. Specific substrates are prepared for each enzyme,namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide andSuc-Ala-Ala-Pro-Phe-p-nitroanilide. The latter is not hydrolyzed byleukocyte elastase. Enzyme preparations are assayed in 2.00 mL of 0.10 MHepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethylsulfoxide and0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysisof the p-nitroanilide substrate is monitored at 405 nm and at 25° C.

[0262] Useful dose range for the application of compounds of the presentinvention as neutrophil elastase inhibitors and as Cathepsin Ginhibitors depend upon the nature and severity of the disease state, asdetermined by the attending diagnostician, with a range of 0.01 to 10mg/kg body weight, per day, being useful for the aforementioned diseasestates.

[0263] Compounds of the present invention that inhibit urokinase orplasminogen activator are potentially useful in treating excessive cellgrowth disease state. As such compounds of the present invention mayalso be useful in the treatment of benign prostatic hypertrophy andprostatic carcinoma, the treatment of psoriasis, and as abortifacients.For their end-use application, the potency and other biochemicalparameters of the enzyme inhibiting characteristics of compounds of thepresent invention are readily ascertained by standard biochemicaltechniques well known in the art. Actual dose ranges for thisapplication will depend upon the nature and severity of the diseasestate of the patient or animal to be treated as determined by theattending diagnostician. It is to be expected that a general dose rangewill be about 0.01 to 10 mg per kg per day for an effective therapeuticeffect.

[0264] Additional uses for compounds of the present invention includeanalysis of commercial reagent enzymes for active site concentration.For example, chymotrypsin is supplied as a standard reagent for use inclinical quantitation of chymotrypsin activity in pancreatic juices andfeces. Such assays are diagnostic for gastrointestinal and pancreaticdisorders. Pancreatic elastase is also supplied commercially as areagent for quantitation of α₁-antitrypsin in plasma. Plasmaα₁-antitrypsin increases in concentration during the course of severalinflammatory diseases, and α₁-antitrypsin deficiencies are associatedwith increased incidence of lung disease. Compounds of the presentinvention can be used to enhance the accuracy and reproducibility ofthese assays by titrametric standardization of the commercial elastasesupplied as a reagent. See, U.S. Pat. No. 4,499,082.

[0265] Protease activity in certain protein extracts during purificationof particular proteins is a recurring problem which can complicate andcompromise the results of protein isolation procedures. Certainproteases present in such extracts can be inhibited during purificationsteps by compounds of the present invention, which bind tightly tovarious proteolytic enzymes.

[0266] The pharmaceutical compositions of the invention can beadministered to any animal that can experience the beneficial effects ofthe compounds of the invention. Foremost among such animals are humans,although the invention is not intended to be so limited.

[0267] The pharmaceutical compositions of the present invention can beadministered by any means that achieve their intended purpose. Forexample, administration can be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.Alternatively, or concurrently, administration can be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

[0268] In addition to the pharmacologically active compounds, the newpharmaceutical preparations can contain suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries thatfacilitate processing of the active compounds into preparations that canbe used pharmaceutically.

[0269] The pharmaceutical preparations of the present invention aremanufactured in a manner that is, itself, known, for example, by meansof conventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

[0270] Suitable excipients are, in particular, fillers such assaccharides, for example, lactose or sucrose, mannitol or sorbitol,cellulose preparations and/or calcium phosphates, for example,tricalcium phosphate or calcium hydrogen phosphate, as well as binders,such as, starch paste, using, for example, maize starch, wheat starch,rice starch, potato starch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents can be added,such as, the above-mentioned starches and also carboxymethyl-starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as, sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as, magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings that, if desired, are resistant to gastric juices. Forthis purpose, concentrated saccharide solutions can be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethyleneglycol, and/or titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. In order to produce coatings resistant togastric juices, solutions of suitable cellulose preparations, such as,acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate,are used. Dye stuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or in order to characterizecombinations of active compound doses.

[0271] Other pharmaceutical preparations which can be used orallyinclude push-fit capsules made of gelatin, as well as soft, sealedcapsules made of gelatin and a plasticizer, such as, glycerol orsorbitol. The push-fit capsules can contain the active compounds in theform of granules that may be mixed with fillers such as lactose, binderssuch as starches, and/or lubricants such as talc or magnesium stearateand, optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as, fattyoils or liquid paraffin. In addition, stabilizers may be added.

[0272] Suitable formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form, forexample, water-soluble salts, alkaline solutions and cyclodextrininclusion complexes. Especially preferred alkaline salts are ammoniumsalts prepared, for example, with Tris, choline hydroxide, Bis-Trispropane, N-methylglucamine, or arginine. One or more modified orunmodified cyclodextrins can be employed to stabilize and increase thewater solubility of compounds of the present invention. Usefulcyclodextrins for this purpose are disclosed in U.S. Pat. Nos.4,727,064, 4,764,604, and 5,024,998.

[0273] In addition, suspensions of the active compounds as appropriateoily injection suspensions can be administered. Suitable lipophilicsolvents or vehicles include fatty oils, for example, sesame oil, orsynthetic fatty acid esters, for example, ethyl oleate or triglyceridesor polyethylene glycol-400 (the compounds are soluble in PEG-400).Aqueous injection suspensions can contain substances that increase theviscosity of the suspension, for example, sodium carboxymethylcellulose, sorbitol, and/or dextran. Optionally, the suspension may alsocontain stabilizers.

[0274] Compounds of Formula VII can be labeled with radioactive iodineas described below in Example 3 or by using an exchange reaction.Exchange of hot iodine for cold iodine is well known in the art.Alternatively, a radio iodine labeled compound can be prepared from thecorresponding bromo compound via a tributylstannyl intermediate. See,U.S. Pat. No. 5,122,361, herein incorporated by reference.

[0275] The present invention also includes compositions which are usefulfor in vivo imaging of thrombi in a mammal, wherein the compositions arecomprised of a compound of Formula VII complexed with a radioactiveatom.

[0276] For the compounds of Formula VII, suitable radioactive atomsinclude Co-57, Cu-67, Ga-67, Ga-68, Ru-97, Tc-99m, In-111, In-113m,Hg-197, Au-198, and Pb-203. In particular, technetium-99m (Tc-99m) is anideal radioactive atom for imaging because of its nuclear properties. Itis a gamma emitter and has a single photon energy of 140 keV, ahalf-life of about 6 hours, and it is readily available from aMo-99/Tc-99 generator. Rhenium-186 and -188 also have gamma emissionwhich allows them to be imaged. Preferred compositions contain theradioactive atom, Tc-99m.

[0277] Compositions of the present invention are conveniently preparedby completing a compound of Formula VII with radioisotopes which aresuitable for detection externally.

[0278] The compounds of Formula VII can be labeled by any of the manytechniques known in the art to provide a composition of the presentinvention. For example, these compounds can be labeled through achelating agent such as diethylene-triaminepentaacetic acid (DTPA) ormetallothionein, both of which can be covalently attached to thecompound of Formula VII.

[0279] In general, the compositions of the present invention containingtechnetium-99m are prepared by forming an aqueous mixture oftechnetium-99m and a reducing agent and a water-soluble ligand, and thencontacting the mixture with a compound of the present inventionrepresented by Formula VII. For example, the imaging compounds of thisinvention are made by reacting technetium-99m (in an oxidized state)with the compounds of the present invention having a chelating means inthe presence of a reducing agent to form a stable complex betweentechnetium-99m in a reduced state (IV or V valence state).

[0280] One embodiment of the composition of the present invention isprepared by labeling a compound of Formula VII having a DTPA chelatingmeans with technetium-99m. This may be accomplished by combining apredetermined amount (as 5 μg to 0.5 mg) of compound of the presentinvention with an aqueous solution containing citrate buffer andstannous reducing agent, then adding freshly eluted sodium pertechnetatecontaining a predetermined level of radioactivity (as 15 mCi). Afterallowing an incubation of the mixture at room temperature, the reactionmixture is loaded into a shielded syringe through a sterile filter(0.2-0.22 micron), then is dispensed into 0.9% saline for injection, ifdesired.

[0281] Another embodiment of the compositions of the present inventionis prepared by labeling a compound of Formula VII having ametallothionein chelating means with technetium-99m. This may beaccomplished by combining aqueous sodium pertechnetate-99m with aqueousstannous glucoheptonate to form a soluble complex of technetium-99m (inreduced state) with two glucoheptonate molecules, then combining thissolution with a compound of the Formula VII having a metallothioneinattached thereto. After incubating the mixture for a period of time andunder conditions which allow for an exchange of the technetium-99m fromthe glucoheptonate complex to the metallothionein of the compound ofFormula VII, the technetium-labeled composition of the present inventionis formed.

[0282] The source of technetium-99m should preferably be water soluble.Preferred sources are alkali and alkaline earth metal pertechnetate(TcO₄ ⁻). Technetium-99m is most preferably obtained in the form offresh sodium pertechnetate from a sterile technetium-99m generator (asfrom a conventional Mo-99/Tc-99m generator). However, any other sourceof physiologically acceptable technetium-99m may be used.

[0283] Reducing agents for use in the method are physiologicallyacceptable for reducing technetium-99m from its oxidized state to the IVor V valence state or for reducing rhenium from its oxidized state.Reducing agents which can be used are stannous chloride, stannousfluoride, stannous glucoheptonate, stannous tartarate, and sodiumdithionite. The preferred agents are stannous reducing agents,especially stannous chloride or stannous glucoheptonate. For example,stannous chloride (SnCl₂) is the reducing agent and can be used in rangefrom 1-1,000 μg/mL. Especially preferred concentrations are about 30-500μg/mL.

[0284] Citric acid complexes with technetium-99m to quickly form astable technetium-99m-citrate complex. Upon contact with a compound ofFormula VII, substantially quantitative transfer of technetium-99m fromits citrate complex to the chelating means of the compound of FormulaVII is achieved rapidly and under mild conditions. The amount of citricacid (as sodium citrate) can range from about 0.5 mg/ml up to the amountmaximally soluble in the medium. Preferred amounts of citric acid rangefrom 15 to 30 μg/ml.

[0285] The amount of compound of Formula VII having a chelating meanscan range from 0.001 to about 3 mg/mL, preferably about 0.017 to about0.15 mg/mL. Finally, technetium-99m in the form of pertechnetate can beused in amounts of preferably about 1-50 mCi. The amount of mCi per mgof compound of the present invention is preferably about 30-150.

[0286] Alternative compositions of the present invention include anIn-111 labeled compound of the present invention.

[0287] The present invention also includes compositions of the compoundsof the present invention which are useful for in vivo imaging of thrombiin a mammal, comprised of a compound represented by Formula VIIcomplexed to a paramagnetic atom.

[0288] Preferred paramagnetic atoms are divalent or trivalent ions ofelements with an atomic number of 21 to 29, 42, 44 and 58 to 70.Suitable ions include chromium(III), manganese(II), iron(III), iron(II),cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III),samarium(III) and ytterbium(III). Because of their very strong magneticmoments, gadolinium(III), terbium(III), dysoprosium(III), holmium(III),and erbium(III) are preferred. Especially preferred for the paramagneticatom is gadolinium(III).

[0289] The compositions of the present invention may be prepared bycombining a compound of Formula VII with a paramagnetic atom. Forexample, the metal oxide or a metal salt (for example, nitrate, chlorideor sulfate) of a suitable paramagnetic atom is dissolved or suspended ina medium comprised of water and an alcohol, such as methyl, ethyl orisopropyl alcohol. This mixture is added to a solution of an equimolaramount of the compound of Formula VII in a similar aqueous medium andstirred. The reaction mixture may be heated moderately until thereaction is completed. Insoluble compositions formed may be isolated byfiltering, while soluble compositions may be isolated by evaporation ofthe solvent. If acid groups on the chelating means are still present inthe composition of the present invention, inorganic or organic bases,and even amino acids, may be added to convert the acidic complex into aneutral complex to facilitate isolation or purification of homogenouscomposition. Organic bases or basic amino acids may be used asneutralizing agents, as well as inorganic bases such as hydroxides,carbonates or bicarbonates of sodium, potassium or lithium.

[0290] The present invention also include diagnostic compositions whichare useful for in vivo imaging of thrombi in a mammal, comprising apharmaceutically acceptable carrier and a diagnostically effectiveamount of a radiolabeled compound of Formula VII. Compositions such asthose described above may be conveniently used in these diagnosticcompositions.

[0291] The “diagnostically effective amount” of the composition requiredas a dose will depend on the route of administration, the type of mammalbeing treated, and the physical characteristics of the specific mammalunder consideration. These factors and their relationship to determiningthis dose are well known to skilled practitioners in the medialdiagnostic arts. Also, the diagnostically effective amount and method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors which those skilled in the medical arts will recognize. In anyregard, the dose for imaging should be sufficient for detecting thepresence of the imaging agent at the site of a thrombus in question.Typically, radiologic imaging will require that the dose provided by thepharmaceutical composition position of the present invention be about 5to 20 μCi, preferably about 10 μCi. Magnetic resonance imaging willrequire that the dose provided be about 0.001 to 5 mmole/kg, preferablyabout 0.005 to 0.5 mmole/kg of a compound of Formula VII complexed withparamagnetic atom. In either case, it is known in the art that theactual dose will depend on the location of the thrombus.

[0292] “Pharmaceutically acceptable carriers” for in vivo use are wellknown in the pharmaceutical art, and are described, for example, inRemington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985).

[0293] The present invention also encompasses diagnostic compositionsprepared for storage or administration. These would additionally containpreservatives, stabilizers and dyes. For example, sodium benzoate,sorbic acid and esters of p-hydroxybenzoic acid may be added aspreservatives. Id. At 1449. In addition, antioxidants and suspendingagents may be used.

[0294] The in vivo imaging methods of the present invention also offerseveral advantages over previous imaging techniques for the detection ormonitoring of the presence, size, regression or increase of a thrombus.In particular, the present invention provides compounds, compositionsand diagnostic compositions have been designed to bind extremely tightlyto the thrombin associated with a thrombus and thereby reduce“background” due to circulating radioactivity or paramagnetism arisingfrom unbound imaging agent. Furthermore, in vivo imaging byintracoronary injection of the compounds, compositions or diagnosticcompositions of the present invention, is expected to be almostinstantaneous since these imaging agents would saturate the thrombinbound to the thrombus immediately.

[0295] Accordingly, the present invention also includes methods for invivo imaging of a thrombus in a mammal, comprising the steps of: (1)administering to a mammal a diagnostically acceptable amount of acompound, composition, or diagnostic composition of the presentinvention and (2) detecting a thrombus in a blood vessel.

[0296] In employing the compounds, compositions or diagnosticcompositions in vivo by this method, “administering” is accomplishedparenterally, in either a systemic or local targeted manner. Systemicadministration is accomplished by injecting the compounds, compositionsby diagnostic compositions of the present invention into a convenientand accessible vein or artery. This includes but is not limited toadministration by the ankecubutal vein. Local targeted administration isaccomplished by injecting the compounds, compositions or diagnosticcompositions of the present invention proximal in flow to a vein orartery suspected to contain thrombi distal to the injection site. Thisincludes but is not limited to direct injection into the coronaryarterial vasculature to image coronary thrombi, into the carotid arteryto image thrombi in the cerebral vasculature, or into a pedal vein toimage deep vein thrombosis of the leg.

[0297] Also, the manner of delivery of a composition of the presentinvention to the site of a thrombus is considered within the scope ofthe term “administering”. For example, a compound represented by FormulaVII having a chelating means attached thereto may be injected into themammal, followed at a later time by the radioactive atom thereby formingin vivo at the site of the thrombus the composition comprising thecompound of formula complexed to radioactive atom. Alternatively, acomposition comprising the compound of formula complexed to radioactiveatom may be injected into the mammal.

[0298] The detecting of a thrombus by imaging is made possible by thepresence of radioactive or paramagnetic atoms localized at suchthrombus.

[0299] The radioactive atoms associated with the compositions anddiagnostic compositions of the present invention are preferably imagedusing a radiation detection means capable of detecting gamma radiation,such as a gamma camera or the like. Typically, radiation imaging camerasemploy a conversion medium (wherein the high energy gamma ray isabsorbed, displacing an electron which emits a photon upon its return tothe orbital state), photoelectric detectors arranged in a spatialdetection chamber (to determine the position of the emitted photons),and circuitry to analyze the photons detected in the chamber and producean image.

[0300] The paramagnetic atoms associated with the compositions anddiagnostic compositions of the present invention are detected inmagnetic resonance imaging (MRI) systems. In such systems, a strongmagnetic field is used to align the nuclear spin vectors of the atoms ina patient's body. The field is disturbed by the presence of paramagneticatoms localized at a thrombus and an image of the patient is read as thenuclei return to their equilibrium alignments.

[0301] The following examples are illustrative, but not limiting, of themethod and compositions of the present invention. Other suitablemodifications and adaptations of the variety of conditions andparameters normally encountered and obvious to those skilled in the artare within the spirit and scope of the invention.

EXAMPLE 1

[0302]3-Benzylsulfonylamino-6-methyl-1-[(3-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluorocaetate

[0303] 1. 3-Benzyloxycarbonylamino-6-methyl-2-pyridinone

[0304] Diphenylphosphoryl azide (11.9 mL, 55 mmol) was added to asolution of 2-hydroxy-6-methylpyridine-3-carboxylic acid (7.65 g, 50mmol) and triethylamine (7.7 mL, 55 mmol) in dry dioxane (100 mL) andthe resulting solution was heated to reflux. After 16 h moretriethylamine (7.7 mL, 55 mmol) and benzyl alcohol (5.7 mL, 50 mmol)were added and the solution was refluxed for a further 24 h. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between methylene chloride (200 mL) and brine (100 mL),acidified to pH 1 with 10% HCl. The organic layer was washed withsaturated NaHCO₃ (2×100 mL), brine (100 mL), dried over Na₂SO₄ andfiltered. After evaporating the solvent in vacuo, methanol (100 mL) andhexane (20 mL) were added to the residue, the solid was collected,washed with methanol (50 mL) and dried to give the title compound as awhite solid (7.2 g, 56%). ¹H-NMR (300 MHz, CDCl₃) δ12.82 (s, 1H), 8.06(d, J=7.0 Hz, 1H), 7.69 (s, 1H), 7.42 (m, 5H), 6.09 (d, J=7.5 Hz, 1H),5.22 (s, 2H), 2.32 (s, 3H).

[0305] 2.3-Benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

[0306] tert-Butyl bromoacetate (3.9 g, 20 mmol) was added to a stirredsuspension of 3-benzyloxycarbonylamino-6-methyl-2-pyridinone (5.15 g, 20mmol), as prepared in the preceding step, and Cs₂CO₃ (6.5 g, 20 mmol) inN,N-dimethylformamide (50 mL) and stirred at 40° C. overnight. The solidwas removed by filtration and the filtrate concentrated under highvacuum. The residue was dissolved in ethyl acetate (150 mL), washed withwater (2×50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated invacuo. After evaporating the solvent in vacuo, the residue was purifiedby flash column chromatography (25% ethyl acetate in hexane) to give thetitle compound as a white crystalline solid (4.2 g, 56%). ¹H-NMR (300MHz, CDCl₃) δ7.95 (d, J=7.3 Hz, 1H), 7.76 (s, 1H), 7.37 (m, 5H), 6.09(d, J=7.6 Hz, 1H), 5.19 (s, 2H), 4.75 (s, 2H), 2.32 (s, 3H), 1.47 (s,9H).

[0307] 3. 3-Amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

[0308] A mixture of3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(4.1 g, 11 mmol), as prepared in the preceding step, and 10% Pd/C (400mg) in ethanol (100 mL) was hydrogenated under hydrogen (balloon) for1.5 h. The catalyst was removed by filtration through Celite and thefiltrate concentrated to give the title compound as white solid (2.55 g,97%). ¹H-NMR (300 MHz, CDCl₃) δ6.49 (d, J=7.3 Hz, 1H), 5.92 (d, J=7.3Hz, 1H), 4.75 (s, 2H), 2.19 (s, 3H), 1.47 (s, 9H).

[0309] 4.3-Benzylsulfonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

[0310] To a solution of3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (960 mg, 4.0mmol), as prepared in the preceding step, and N-methylmorpholine (840μL, 8.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonylchloride (765 mg, 4.0 mmol) at 0° C. The reaction mixture was stirred at0° C. for 1 h. Additional methylene chloride (50 mL) was added. Theresulting methylene chloride solution was washed with saturated NaHCO₃(2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried overNa₂SO₄. The solvent was concentrated to give a solid which was washedwith ethyl acetate/hexane (1:2, 60 mL) to give the title compound as awhite solid (1.4 g, 89%). 1H-NMR (300 MHz, CDCl₃) δ7.35 (d, J=7.5 Hz,1H), 7.31 (m, 5H), 7.20 (s, 1H), 6.02 (d, J=7.4 Hz, 1H). 4.75 (s, 2H),4.31 (s, 2H), 2.27 (s, 3H), 1.51 (s, 9H).

[0311] 5. 3-Benzylsulfonylamino-6-methyl-1-carboxymethyl-2-pyridinone

[0312] HCl gas was bubbled through a stirred suspension of3-benzylsulfonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(1.4 g, 3.57 mmol), as prepared in the preceding step, in ethyl acetate(15 mL) at 0° C. until a solution was formed. After 2 h at roomtemperature, a thick suspension was formed. The mixture was degassedwith nitrogen and filtered to give the title compound a white solid (1.1g, 92%). ¹H-NMR (300 MHz, CDCl₃) δ8.67 (s, 1H), 7.34 (m, 5H), 7.12 (d,J=7.5 Hz, 1H), 6.10 (d, J=7.6 Hz, 1H), 4.78 (s, 2H), 4.51 (s, 2H), 2.26(s, 3H).

[0313] 6. 3-(Benzyloxycarbonylamino)-1-propanol

[0314] To a solution of 3-amino-1-propanol (3.75 g, 50 mmol) inmethylene chloride (40 mL) was slowly added benzyl chloroformate (3.4 g,20 mmol) in methylene chloride (10 mL) at 0° C. and the mixture wasstirred at 0° C. for 3 h. Additional methylene chloride (50 mL) wasadded, the solution washed with 10% citric acid (3×50 mL) and brine (50mL), and dried over Na₂SO₄. After evaporating the solvent in vacuo, theresidue was purified by filtration through silica gel (1:1 ethylacetate:hexane) to give the title compound as a white solid (4.05 g,97%). ¹H-NMR (300 MHz, CDCl₃) δ7.34 (m, 5H), 5.17 (br s, 1H), 5.10 (s,2H), 3.66 (t, J=5.8 Hz, 2H), 3.33 (t, J=6.1 Hz, 2H), 2.63 (br s, 1H),1.69 (pentet, J=6.1 Hz, 2H).

[0315] 7. N-[3-(Benzyloxycarbonylamino)-1-propoxy]phthalimide

[0316] To a solution of 3-(benzyloxycarbonylamino)-l-propanol (4.0 g, 19mmol), as prepared in the preceding step, N-hydroxyphthalimide (3.26 g,20 mmol) and triphenylphosphine (5.25 g, 20 mmol) in tetrahydrofuran (80mL) was added diethyl azodicaroxylate (3.5 g, 20 mmol). The reactionmixture was stirred at room temperature overnight. Ethyl acetate (200mL) was added, the solution washed with saturated NaHCO₃ (2×100 mL) andbrine (100 mL), and dried over Na₂SO₄. After evaporating the solvent,the residue was purified by flash column chromatography (methylenechloride to 4% ethyl acetate in methylene chloride) to give the titlecompound as a white solid (6.85 g, 100%). ¹H-NMR (300 MHz, CDCl₃) δ7.83(m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28(t, J=5.8 Hz, 2H), 3.51 (q, J=6.1 Hz, 2H), 1.99 (pentet, J=6.0 Hz, 2H).

[0317] 8. 3-(Benzyloxycarbonylamino)-1-propoxyamine

[0318] To a solution ofN-[3-(benzyloxycarbonylamino)-1-propoxy]phthalimide (1.42 g, 4.0 mmol),as prepared in the preceding step, in ethanol (20 mL) andtetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25 mmol). Thesolution was stirred at room temperature for 1 h. The solvent wasevaporated and the residue passed through silica gel (3:1 ethylacetate:hexane to ethyl acetate) to give the title compound as a whitesolid (870 mg, 97%). ¹H-NMR (300 MHz, CDCl₃) δ7.36 (m, 5H), 5.38 (br s,2H), 5.09 (s, 2H), 5.08 (br s, 1H), 3.73 (t, J=5.9 Hz, 2H), 3.29 (q,J=6.2 Hz, 2H), 1.79 (pentet, J=6.2 Hz, 2H).

[0319] 9. [N,N′-Di(tert-butoxycarbonyl)]3-(benzyloxycarbonylamino)-1-propoxyguanidine

[0320] To a solution of 3-(benzyloxycarbonylamino)-1-propoxyamine (860mg, 3.84 mmol), as prepared in the preceding step, inN,N-dimethylformamide (20 mL) was added[N,N′-di(tert-butoxycarbonyl)]amidinopyrazole (1.25 g, 4.0 mmol). Themixture was stirred at room temperature overnight, the solvent wasevaporated under high vacuum and the residue was purified by flashcolumn chromatography (0-5% ethyl acetate in methylene chloride) to givethe title compound as a colorless oil (1.60 g, 89%). ¹H-NMR (300 MHz,CDCl₃) δ9.10 (br s, 1H), 7.74 (br s, 1H), 7.35 (m, 5H), 5.55 (br s, 1H),5.10 (s, 2H), 4.12 (t, J=6.1 Hz, 2H), 3.32 (t, J=6.4 Hz, 2H), 1.87(pentet, J=6.2 Hz, 2H), 1.50 (s, 9H), 1.47 (s, 9H).

[0321] 10. [N,N′-Di(tert-butoxycarbonyl)] 3-amino-1-propoxyguanidine

[0322] A mixture of [N,N′-di(tert-butoxycarbonyl)]3-(benzyloxycarbonylamino)-1-propoxyguanidine (760 mg, 1.7 mmol), asprepared in the preceding step, and 10% Pd/C (80 mg) in ethanol (20 mL)and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon)for 30 min. The catalyst was removed by filtration through Celite, thefiltrate was concentrated in vacuo, and the residue was purified byWaters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated withammonia) to give the title compound as a colorless oil (160 mg, 28%).¹H-NMR (300 MHz, CDCl₃) δ4.12 (t, J=6.1 Hz, 2H), 2.85 (t, J=6.7 Hz, 2H),1.84 (pentet, J=6.2 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).

[0323] 11.3-Benzylsulfonylamino-6methyl-1-{[N,N′-di(tert-butoxycarbonyl)][3-(guanidinooxypropyl)aminocarbonylmethyl]}-2-pyridinone

[0324] To a solution of3-benzylsulfonylamino-6-methyl-1-carboxymethyl-2-pyridinone (152 mg,0.45 mmol), as prepared in the step 5, [N,N′-di(tert-butoxycarbonyl)]3-amino-1-propoxyguanidine (150 mg, 0.45 mmol), as prepared in thepreceding step, and diisopropylethylamine (90 μL, 0.5 mmol) inN,N-dimethylformamide (10 mL) was added Castro's reagent (BOP) (221 mg,0.5 mmol). The mixture was stirred at room temperature overnight. Ethylacetate (100 mL) was added, the solution washed with saturated NaHCO₃(2×50 mL), 10% citric acid (2×50 mL) and brine (50 mL), and dried overNa₂SO₄. After evaporating the solvent in vacuo, the residue was purifiedby Waters Sep-Pak (10 g, 4:1 ethyl acetate:hexane) to give the titlecompound as a colorless foam (270 mg, 92%). ¹H-NMR (300 MHz, CDCl₃)δ9.02 ( s, 1H), 8.70 (s, 1H), 8.58 (s, 1H), 8.27 (t, J=5.6 Hz, 1H), 7.34(m, 5H), 7.12 (d, J=7.6 Hz, 1H), 6.08 (d, J=7.7 Hz, 1H), 4.70 (s, 2H),4.50 (s, 2H), 3.88 (t, J=6.3 Hz, 2H), 3.18 (t, J=6.4 Hz, 2H), 2.24 (s,3H), 1.75 (t, J=6.5 Hz, 2H), 1.39 (s, 18H).

[0325] 12. 3-Benzylsulfonylamino-6-methyl-1-[(3-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0326] A mixture of3-benzylsulfonylamino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][3-(guanidinooxypropyl)aminocarbonylmethyl]}-2-pyridinone (130 mg, 0.2mmol), as prepared in the preceding step, and trifluoroacetic acid (2mL) in methylene chloride (5 mL) was stirred at room temperature for 1h. After evaporating the solvent in vacuo, the residue was purified byWaters Sep-Pak (10 g, 10% methanol in methylene chloride) to give thetitle compound as a colorless foam (55 mg, 61%). ¹H-NMR (300 MHz,DMSO-d₆) δ8.57 (s, 1H), 8.35 (t, J=5.7 Hz, 1H), 7.62 (br s, 4H), 7.34(m, 5H), 7.12 (d, J=7.5 Hz, 1H), 6.09 (d, J=7.7 Hz, 1H), 4.70 (s, 2H),4.52 (s, 2H), 3.81 (t, J=6.4 Hz, 2H), 3.20 (q, J=6.4 Hz, 2H), 2.25 (s,3H), 1.77 (pentet, J=6.5 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉H₂₆N₆O₅S: 451.2(M+H), 473.2 (M+Na); Found: 451.5, 473.5.

EXAMPLE 2

[0327]3-Benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0328] 1. N-[2-(Benzyloxycarbonylamino)ethoxy]phthalimide

[0329] To a solution of benzyl N-(2-hydroxyethyl)carbamate (5.9 g, 30mmol), N-hydroxyphthalimide (4.9 g, 30 mmol), and triphenylphosphine(7.9 g, 30 mmol) in tetrahydrofuran (100 mL) was added diethylazodicarboxylate (5.2 g, 30 mmol). The reaction mixture was stirred atroom temperature overnight. Ethyl acetate (200 mL) was added, thesolution washed with saturated NaHCO₃ (2×100 mL) and brine (100 mL), anddried over Na2SO₄. After evaporating the solvent, the residue waspurified by flash column chromatography (methylene chloride to 4% ethylacetate in methylene chloride) to give the title compound as a whitesolid (9.3 g, 91%). ¹H-NMR (300 MHz, CDCl₃) δ7.84 (m, 2H), 7.78 (m, 2H),7.37 (m, 5H), 5.97 (br s, 1H), 5.14 (s, 2H), 4.27 (t, J=4.9 Hz, 2H), 3.5(q, J=5.2 Hz, 2H).

[0330] 2. 2-(Benzyloxycarbonylamino)ethoxyamine

[0331] To a solution of N-[2-(benzyloxycarbonylamino)ethoxy]phthalimide(1.36 g, 4.0 mmol), as prepared in the preceding step, in ethanol (20mL) and tetrahydrofuran (20 mL) was added 40% methylamnine (2 mL, 25mmol). The reaction mixture was stirred at room temperature for 1 h.After evaporating the solvent, the residue was passed through silica gel(3:1 ethyl acetate:hexane to ethyl acetate) to give the title compoundas a white solid (800 mg, 95%). ¹H-NMR (300 MHz, CDCl₃) δ7.36 (m, 5H),5.47 (br s, 2H), 5.21 (br s, 1H), 5.10 (s, 2H), 3.72 (t, J=5.0 Hz, 2H),3.44 (q, J=5.0 Hz, 2H).

[0332] 3. [N,N′-Di(tert-butoxycarbonyl)] 2-(benzyloxycarbonylamino)ethoxyguanidine

[0333] To a solution of 2-(benzyloxycarbonylamino)ethoxyamine (780 mg,3.7 mmol), as prepared in the preceding step, in N,N-dimethylformamide(20 mL) was added [N,N′-di(tert-butoxycarbonyl)] amidinopyrazole (1.25g, 4.0 mmol). The mixture was stirred at room temperature overnight, thesolvent was evaporated under high vacuum. The residue was purified byflash column chromatography (0-5% ethyl acetate in methylene chloride)to give the title compound as a colorless oil (1.55 g, 93%). ¹H-NMR (300MHz, CDCl₃) δ9.08 (s, 1H), 7.67 (s, 1H), 7.33 (m, 5H), 6.21 (br s, 1H),5.21 (br s, 1H), 5.11 (s, 2H), 4.12 (t, J=4.8 Hz, 2H), 3.54 (q, J=4.9Hz, 2H), 1.49 (s, 9H), 1.46 (s, 9H).

[0334] 4. [N,N′-Di(tert-butoxycarbonyl)] 2-aminoethoxyguanidine

[0335] A mixture of [N,N′-di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)-ethoxyguanidine (730 mg, 1.5 mmol), asprepared in the preceding step, and 10%c Pd/C (70 mg) in ethanol (20 mL)and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon)for 30 min. The catalyst was removed by filtration through Celite andthe filtrate was concentrated in vacuo. The residue was purified byWaters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated withammonia) to give the title compound as a colorless oil (290 mg, 61%).¹H-NMR (300 MHz, CDCl₃) δ9.08 (br s, 1H), 4.08 (t, J=5.2 Hz, 2H), 2.99(q, J=5.1 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).

[0336] 5.3-Benzylsulfonylamino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

[0337] To a solution of3-benzylsulfonylamino-6-methyl-1-carboxymethyl-2-pyridinone (152 mg,0.45 mmol), as prepared in the step 5 of Example 1,[N,N′-di(tert-butoxycarbonyl)] 2-aminoethoxyguanidine (143 mg, 0.45mmol), as prepared in the preceding step, diisopropylethylamine (90 μL,0.5 mmol) in N,N-dimethylformamide (10 mL) was added Castro's reagent(BOP) (221 mg, 0.5 mmol). The mixture was stirred at room temperatureovernight. Ethyl acetate (100 mL) was added, the solution was washedwith saturated NaHCO₃ (2×50 mL), 10% citric acid (2×50 mL) and brine (50mL), and dried over Na₂SO₄. After evaporating the solvent in vacuo, theresidue was purified by Waters Sep-Pak (10 g, 4:1 ethyl acetate:hexane)to give the title compound as a colorless foam (270 mg, 94%). ¹H-NMR(300 MHz, CDCl₃) δ9.22 (s, 1H), 8.41 (t, J=5.0 Hz, 1H), 8.02 (s, 1H),7.62 (s, 1H), 7.34 (s, 1H), 7.29 (m, 5H), 5.99 (d, J=7.7 Hz, 1H), 4.89(s, 2H), 4.31 (s, 2H), 4.13 (t, J=5.0 Hz, 2H), 3.62 (q, J=5.1 Hz, 2H),2.30 (s, 3H), 1.52 (s, 9H), 1.48 (s, 9H).

[0338] 6. 3-Benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0339] A mixture of3-benzylsulfonylamino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone (255 mg, 0.4mmol), as prepared in the preceding step, and trifluoroacetic acid (4mL) in methylene chloride (8 mL) was stirred at room temperature for 1h. After evaporating the solvent in vacuo, the residue was purified byWaters Sep-Pak (10 g, 10% methanol in methylene chloride) to give thetitle compound as a colorless foam (160 mg, 92%). ¹H-NMR (300 MHz,DMSO-d₆) δ8.58 (s, 1H), 8.49 (t, J=5.5 Hz, 1H), 7.73 (br s, 4H), 7.35(m, 5H), 7.13 (d, J=7.6 Hz, 1H), 6.11 (d, J=7.7 Hz, 1H), 4.74 (s, 2H),4.52 (s, 2H), 3.84 (t, J=5.3 Hz, 2H), 3.40 (m, 2H), 2.26 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₂₄N₆O₅S: 437.2 (M+H), 459.1 (M+Na); Found: 437.3, 459.2.

EXAMPLE 3

[0340]

[0341] a. A solution of the amine, 1 (0.025 g, 0.052 mmol) indichloromethane (2 mL) was treated with diethylaminoethyl polystyreneresin (Fluka, 0.033 g, 0.098 mmol) and 4-iodobenzenesulfonyl chloride(0.03 g, 0.1 mmol). The mixture was shaken at ambient temperature forfive hours before aminomethyl polystyrene resin. (Adv. Chem. Tech., 0.1g, 0.2 mmol) was added as a scavenger of excess sulfonyl chloride.Additional dichloromethane (2 mL) was added and the mixture was shakenovernight. The reaction mixture, including the resins, was poured onto asilica gel column (5 g SepPak) and eluted with a gradient of 10 to 50%ethyl acetate in dichloromethane. The appropriate fractions werecollected and evaporated to dryness on a Savant. Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₇H₃₇N₆O₉SI—2 t-Boc: 549.1. Found: 549.3.

[0342] b. A solution of the sulfonamide, 2 in dichloromethane (2 mL) wastreated with trifluoroacetic acid (1 mL) at ambient temperature andshaken for 4 h. The dichloromethane was removed on a Savant and theresidue was purified on a silica gel column (5 g SepPak) by elution with5% methanol in dichloromethane. The appropriate fractions were combinedand evaporated to dryness to give 19.6 mg (69% yield over 2 steps) of 3as a gum. ¹H-NMR (300 Mhz, CDCl₃) δ10.95 (s, 1H), 9.48 (s, 1H), 8.42 (t,2H, J=5.6 Hz), 7.90 (d, 2H, J=8.6 Hz), 7.72 (s, 4H), 7.56 (d, 2H, J=8.6Hz), 7.26 (d, 1H, J=7.5 Hz), 6.10 (d, 1H, J=7.7 Hz), 4.60 (s, 2H), 3.96(s, 2H), 3.80 (t, 2H, J=5.3 Hz), 2.20 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₇H₂₁N₆O₅SI: 549.1. Found: 549.0.

[0343] c. [I-125]p-Iodobenzene sulfonyl chloride (A. S. Keston et al.,J. Amer. Chem. Soc. 68:1390 (1946)) can be substituted in step a for thecold-iodo compound to form [I-125]3.

EXAMPLE 4

[0344]3-Benzylsulfonylamino-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0345] 1.3-Benzylsulfonylamino-1-(tert-butoxycarbonylmethyl)-2-pyridinone

[0346] To a solution of3-amino-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.12 g, 5.0 mmol),and N-methylmorpholine (1.5 mL, 10.0 mmol) in methylene chloride (40 mL)was added α-toluenesulfonyl chloride (950 mg, 5.0 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 1 h. Additional methylenechloride (50 mL) was added. The resulting solution was washed withsaturated NaHCO₃ (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL),and dried over Na₂SO₄ and filtered and the filtrate was concentrated togive a solid which was washed with ethyl acetate/hexane (1:2, 60 mL) togive the title compound as a white solid (1.8 g, 96%). ¹H-NMR (300 MHz,CDCl₃) δ7.42 (br s, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.31 (m, 5H), 6.92 (d,J=7.0 Hz, 1H), 6.14 (t, J=7.2 Hz, 1H), 4.58 (s, 2H), 4.34 (s, 2H), 1.51(s, 9H).

[0347] 2. 3-Benzylsulfonylamino-1-carboxymethyl-2-pyridinone

[0348] HCl gas was bubbled through a stirred suspension of3-benzylsulfonylamino-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.7 g,4.5 mmol), as prepared in the preceding step, in ethyl acetate (15 mL)at 0° C. until a solution was formed. After 2 h at room temperature, athick suspension was formed. The mixture was degassed with nitrogen andfiltered to give the title compound a white solid (1.4 g, 97%). ¹H-NMR(300 MHz, CDCl₃) δ8.76 (s, 1H), 7.45 (dd, J=7.0, 1.8 Hz, 1H), 7.32 (m,5H), 7.19 (dd, J=7.2, 1.8 Hz, 1H), 6.16 (t, J=7.1 Hz, 1H), 4.69 (s, 2H),4.56 (s, 2H).

[0349] 3. 3Benzylsulfonylamino-1-([N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl])-2-pyridinone

[0350] To a solution of3-benzylsulfonylamino-1-carboxymethyl-2-pyridinone (129 mg, 0.4 mmol),as prepared in the preceding step, [N,N′-di(tert-butoxycarbonyl)]2-aminoethoxyguanidine (143 mg, 0.45 mmol), as prepared in step 4 ofExample 2, diisopropylethylamine (90 μL, 0.5 mmol) inN,N-dimethylformamide (10 mL) was added Castro's reagent (BOP) (221 mg,0.5 mmol). The mixture was stirred at room temperature overnight. Ethylacetate (100 mL) was added, the solution was washed with saturatedNaHCO₃ (2×50 mL), 10% citric acid (2×50 mL) and brine (50 mL), and driedover Na₂SO₄. After evaporating the solvent in vacuo, the residue waspurified by Waters Sep-Pak (10 g, 4:1 ethyl acetate:hexane) to give thetitle compound as a colorless foam (170 mg, 68%). ¹H-NMR (300 MHz,CDCl₃) δ9.22 (s, 1H), 8.49 (br s, 1H), 7.44 (s, 1H), 7.34 (dd, J=7.3,1.7 Hz, 1H), 7.29 (m, 5H), 7.02 (dd, J=7.0, 1.7 Hz, 1H), 6.12 (t, J=7.1Hz, 1H), 4.73 (s, 2H), 4.34 (s, 2H), 4.15 (m, 2H), 3.65 (m, 2H), 1.52(s, 9H), 1.49 (s, 9H).

[0351] 4.3-Benzylsulfonylamino-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0352] A mixture of3-benzylsulfonylamino-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone (155 mg, 0.25mmol), as prepared in the preceding step, and trifluoroacetic acid (2mL) in methylene chloride (3 mL) was stirred at room temperature for 2h. After evaporation of the solvent in vacuo, the residue was purifiedby Waters Sep-Pak (10 g, 10% methanol in methylene chloride) to give thetitle compound as a colorless foam (160 mg, 92%). ¹H-NMR (300 MHz,DMSO-d₆) δ11.00 (s, 1H), 8.66 (s, 1H), 8.45 (t, J=5.3 Hz, 1H), 7.72 (brs, 4H), 7.40 (d, J=6.9 Hz, 1H), 7.33 (m, 5H), 7.19 (d, J=7.0 Hz, 1H),6.19 (d, J=7.0 Hz, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.83 (t, J=5.1 Hz,2H), 3.39 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₁₇H₂₂N₆O₅S: 423.1 (M+H), 445.1 (M+Na); Found:423.3, 445.0.

EXAMPLE 5

[0353]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0354] 1.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

[0355] To a solution of3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.42 g,5.88 mmol), as prepared in step 3 of Example 1, and N-methylmorpholine(1.29 mL, 11.76 mmol) in methylene chloride (40 mL) was added3-methylbenzenesulfonyl chloride (1.12 g, 5.88 mmol) at 0° C. Thereaction mixture was stirred at room temperature overnight. Additionalmethylene chloride (60 mL) was added. The resulting methylene chloridesolution was washed with saturated NaHCO₃ (2×50 mL), 10% citric acid(3×50 mL) and brine (50 mL), and dried over Na₂SO₄. After evaporatingthe solvent, the residue was purified by flash column chromatography (5to 10% ethyl acetate in methylene chloride) to give the title compoundas a white solid (2.1 g, 91%). ¹H-NMR (300 MHz, CDCl₃) δ7.63 (m, 2H),7.55 (br s, 1H), 7.42 (d, 1H, J=8 Hz), 7.32 (m, 2H), 6.01 (d, 1H, J=8Hz), 4.64 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.43 (s, 9H).

[0356] 2.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone

[0357] HCl gas was bubbled through a stirred suspension of3-(3-methylphenylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(2.0 g, 5.09 mmol), as prepared in the preceding step, in ethyl acetate(50 mL) at 0° C. until a solution was formed. After warming to roomtemperature over 2 h, a thick suspension was formed. The mixture wasdegassed with nitrogen and filtered to give the title compound as awhite solid (1.36 g, 80%). ¹H-NMR (300 MHz, DMSO-d₆) δ9.38 (s, 1H), 7.62(m, 2H), 7.41 (m, 2H), 7.25 (d, 1H, J=8 Hz), 6.09 (d, 1H, J=8 Hz), 4.67(s, 2H), 2.35 (s, 3H),

[0358] 3.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

[0359] To a solution of3-(3-methylphenylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone(1.26 g, 3.75 mmol), as prepared in the preceding step,[N,N′-di(tert-butoxycarbonyl)] 2-amino-1-ethoxyguanidine hydrochloride(1,33 g, 3.75 mmol) as prepared in step 4 of Example 2, anddiisopropylethylamine (1.29 g, 10.0 mmol) in N,N-dimethylformamide (30mL) was added Castro's reagent (BOP) (2.0 g, 4.47 mmol). The mixture wasstirred at room temperature overnight. Ethyl acetate (150 mL) was added,the solution was washed with saturated NaHCO₃ (2×50 mL), 10% citric acid(2×50 mL) and brine (50 mL), and dried over Na₂SO₄. After evaporatingthe solvent in vacuo, the residue was purified twice by columnchromatography (1:1 ethyl acetate:hexane; then 2% methanol in methylenechloride) to give the title compound as a white solid (2.25 g, 92%).¹H-NMR (300 MHz, CDCl₃) δ9.17 (s, 1H), 8.34 (t, J=5.1 Hz, 1H), 7.66 (m,4H), 7.48 (d, J=7.6 Hz, 1H), 7.32 (m, 2H), 6.00 (d, J=7.7 Hz, 1H), 4.80(s, 2H), 4.10 (t, J=5.3 Hz, 2H), 3.59 (q, J=5.4 Hz, 2H), 2.38 (s, 3H),2.25 (s, 3H), 1.55 (s, 9H), 1.45 (s, 9H).

[0360] 4.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(3-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluorocaetate

[0361] A mixture of3-(3-methylphenylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][3-(guanidinooxypropyl)aminocarbonylmethyl]}-2-pyridinone (2.24 g, 3.44mmol), as prepared in the preceding step, and trifluoroacetic acid (10mL) in methylene chloride (20 mL) was stirred at room temperature for 4h. After evaporating the solvent in vacuo, the residue was purified bycolumn chromatography (10% methanol in methylene chloride) to give thetitle compound as a white solid (1.59 g, 82%). ¹H-NMR (300 MHz, CD₃OD)δ7.61 (m, 2H), 7.47 (d, 1H, J=7.6 Hz), 7.38 (m, 2H), 6.20 (dd, 1H, J=7.7Hz, 0.7 Hz), 4.70 (s, 2H), 3.93 (t, 2H, J=5.2 Hz), 3.48 (t, 2H, J=5.2Hz), 2.37 (s, 3H), 2.29 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₈H₂₄SN₆O₅: 437.5 (M+H); found: 437.2.

[0362] 5.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(3-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride

[0363] 3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(3-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluorocaetate (2.75 g, 5.0 mmol),as prepared in the preceding step, was treated with water (10 mL) andbrine (80 mL). The pH of the mixture was adjusted to 1 with 20%hydrochloride acid, the resulting mixture was stirred until the productcrystallized. The precipitate was collected by filtration, washed withice cold water, and oven dried in vacuo at 45° C. for two days to affordthe title compound as an off-white solid (2.25 g, 95%). mp: 177-179° C.¹H-NMR (300 MHz, DMSO-d₆) δ11.1 (s, 1H), 9.3 (s, 1H), 8.6 (t, J=7.5 Hz,1H), 7.75 (br s, 4H), 7.42 (m, 4H), 7.25 (d, J=7.6 Hz, 1H), 6.10 (d,J=7.7 Hz,1H), 4.65 (s, 2H), 3.80 (t, J=5.2 Hz, 2H), 3.40 (q, J=5.2 Hz,2H), 2.35 (s, 3), 2.24 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₈H₂₄SN₆O₅: 437.5 (M+H); found: 437.2.

EXAMPLE 6

[0364]3-(Benzyloxycarbonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0365] The title compound was prepared form3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone,as prepared in step 2 of Example 1, using the procedures in step 5 ofExample 1 and steps 5 & 6 of Example 2. ¹H-NMR (300 MHz, DMSO-d₆) δ11.03(s, 1H), 8.47 (t, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.76 (br s, 4H), 7.73 (d,J=7.5 Hz, 1H), 7.40 (m, 5H), 6.18 (d, J=7.7 Hz, 1H), 5.15 (s, 2H), 4.73(s, 2H), 3.82 (t, J=5.3 Hz, 2H), 3.38 (m, 2H), 2.24 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₉H₂₄N₆O₅: 417.2 (M+H), 439.2 (M+Na), 455.1 (M+K); Found: 417.3, 439.4,455.4.

EXAMPLE 7

[0366] 3-(Benzylsulfonyl)amino-6-methyl-1-[(1-(1-guanidinooxymethyl)cyclopropyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0367] 1. 1-(Benzyloxycarbonylamino)cyclopropanemethanol

[0368] To a solution of 1-(benzyloxycarbonylamino)cyclopropanecarboxylicacid (500 mg, 2.1 mmol) in tetrahydrofuran (5 mL) at 0° C. was addedB₂H₆. THF (1M, 2.1 mL, 2.1 mmol). The mixture was stirred at ambienttemperature overnight, treated with K₂CO₃ (1.0 g in 5 mL H₂O) andextracted with methylene chloride (3×10 mL). The organic layer waswashed with brine (10 mL) and dried over Na₂SO₄. After evaporating thesolvent, the residue was by chromatography (1:1 ethyl acetate: hexane)to give the title compound as a white solid (200 mg, 43%). ¹H-NMR (300MHz, CDCl₃) δ7.35 (m, 5H), 5.30 (br s, 1H), 5.10 (s, 2H), 3.61 (s, 2H),3.02 (br s, 1H), 0.86 (s, 4H).

[0369] 2. N-[1-(Benzyloxycarbonylamino)cyclopropanemethoxy]phthalimide

[0370] The title compound was prepared from 1-(benzyloxycarbonylamino)cyclopropanemethanol (200 mg, 0.9 mmol), as prepared in the precedingstep, using the procedure in step 1 of Example 2, as a white solid (295mg, 90%). ¹H-NMR (300 MHz, CDCl₃) δ7.83 (m, 2H), 7.79 (m, 2H), 7.37 (m,5H), 6.23 (br s, 1H), 5.13 (s, 2H), 4.18 (s, 2H), 0.93 (m, 2H), 0.72 (m,2H).

[0371] 3. [1-(Benzyloxycarbonylamino)cyclopropanemethoxy]amine

[0372] The title compound was prepared fromN-[1-(benzyloxycarbonylamino) cyclopropanemethoxy]phthalimide (290 mg,0.8 mmol), as prepared in the preceding step, using the procedure instep 2 of Example 2, as a colorless oil (180 mg, 95%). ¹H-NMR (300 MHz,CDCl₃) δ7.35 (m, 5H), 5.60 (br s, 2H), 5.23 (br s, 1H), 5.09 (s, 2H),3.64 (s, 2H), 0.89 (m, 4H).

[0373] 4. [N,N′-Di(tert-butoxycarbonyl)] [1-(benzyloxycarbonylamino)cyclopropanemethoxy]guanidine

[0374] The title compound was prepared from [1-(benzyloxycarbonylamino)cyclopropanemethoxy]amine (180 mg, 0.76 mmol), as prepared in thepreceding step, and (N,N′-di-tert-butoxycarbonyl)amidinopyrazole (280mg, 0.9 mmol) using the procedure in step 3 of Example 2, as a colorlessoil (330 mg, 91%). ¹H-NMR (300 MHz, CDCl₃) δ9.10 (br s, 1H), 8.02 (br s,1H), 7.35 (m, 5H), 5.74 (br s, 1H), 5.09 (s, 2H), 4.03 (s, 2H), 1.49 (s,9H), 1.47 (s, 9H), 0.91 (m, 4H).

[0375] 5. [N,N′-Di(tert-butoxycarbonyl)] (1-aminocyclopropanemethoxy)guanidine

[0376] The title compound was prepared from[N,N′-di(tert-butoxycarbonyl)][1-(benzyloxycarbonylamino)cyclopropanemethoxy]guanidine (330 mg, 0.69mmol), as prepared in the preceding step, using the procedure in step 4of Example 2, as a colorless oil (200 mg, 84%). ¹H-NMR (300 MHz, CDCl₃)δ9.09 (br s, 1H), 3.96 (s, 2H), 1.52 (s, 9H), 1.48 (s, 9H), 0.67 (m,2H), 0.60 (m, 2H).

[0377] 6.3-Benzylsulfonylamino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][1-(1-(guanidinooxymethyl)cyclopropylamino)carbonylmethyl]}-2-pyridinone

[0378] The title compound was prepared from[N,N′-di(tert-butoxycarbonyl)] (1-aminocyclopropanemethoxy)guanidine(100 mg, 0.3 mmol), as prepared in the preceding step, and3-benzylsulfonylamino-6-methyl-1-carboxymethyl-2-pyridinone (100 mg, 0.3mmol), as prepared in the step 5 of Example 1, using the procedure instep 5 of Example 2, as a colorless foam (120 mg, 60%). ¹H-NMR (300 MHz,CDCl₃) δ9.08 (br s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.31 (d, J=7.5 Hz,1H), 7.26 (m, 5H), 6.00 (d, J=7.7 Hz, 1H), 4.79 (s, 2H), 4.30 (s, 2H),3.97 (s, 2H), 2.31 (s, 3H), 1.51 (s, 9H), 1.48 (s, 9H), 1.04 (m, 2H),0.87 (m, 2H).

[0379] 7. 3-(Benzylsulfonyl)amino-6-methyl-1-[(1-(1-guanidinooxymethyl)cyclopropyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0380] The title compound was prepared form3-benzylsulfonylamino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][1-(1-(guanidinooxymethyl)cycloamino)carbonylmethyl]}-2-pyridinone (110mg, 0.166 mmol), as prepared in the preceding step, using the procedurein step 6 of Example 2, as a white solid (85 mg, 89%). ¹H-NMR (300 MHz,DMSO-d₆) δ1.88 (br s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 7.73 (br s, 4H),7.33 (m, 5H), 7.13 (d, J=7.5 Hz, 1H), 6.11 (d, J=7.7 Hz, 1H), 4.71 (s,2H), 4.50 (s, 2H), 3.80 (s, 2H), 2.23 (s, 3H), 0.86 (m, 2H), 0.78 (m,2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₂₀H₂₆N₆O₅S: 463.2 (M+H), 485.2 (M+Na); Found: 463.1, 485.2.

EXAMPLE 8

[0381] 3-(Benzylsulfonyl)amino-6-methyl-1-[(4-guanidinooxy)piperidinylcarbonylmethyl]-2-pyridinone trifluoroacetate

[0382] The title compound was prepared from 4-hydroxypiperidine usingthe procedures in steps 6-10 of Example 1 and steps 5 & 6 of Example 2,as a colorless foam. ¹H-NMR (300 MHz, DMSO-d₆) δ11.14 (s, 1H), 8.57 (s,1H), 7.74 (br s, 4H), 7.34 (m, 5H), 7.12 (d, J=7.6 Hz, 1H), 6.09 (d,J=7.9 Hz, 1H), 5.02 (s, 2H), 4.52 (s, 2H), 3.89 (m, 3H), 3.36 (m, 1H),3.13 (m, 1H), 2.20 (s, 3H), 2.00 (m, 1H), 1.81 (m, 1H), 1.72 (m, 1H),1.56 (m, 1H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₁H₂₈N₆O₅S: 477.2 (M+H), 499.2 (M+Na), 515.1 (M+K);Found: 477.0, 498.9, 514.9

EXAMPLE 9

[0383] 3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0384] 1. 3-Chlorobenzylsulfonyl chloride

[0385] A mixture of 3-chlorobenzyl chloride (1.61 g, 10 mmol) and sodiumthiosulfate (1.6 g, 10 mmol) in methanol (10 mL) and water (10 mL) washeated to reflux for 3 h. The mixture was cooled to 0° C. and glacialacetic acid (10 mL) and ice were added. Chlorine gas was bubbled throughthe resulting suspension for 40 min, periodically adding ice to maintainan ice/liquid mixture. After an additional 1 h, the mixture wasextracted with ether (3×20 mL), the combined extracts were washed with5% sodium bisulfite (2×20 mL), brine (20 mL) and dried over Na₂SO₄.After evaporating the solvent, the residue was purified by flash columnchromatography (methylene chloride) to give the title compound as awhite solid (1.5 g, 67%). ¹H-NMR (300 MHz, CDCl₃) δ7.30-7.50 (m, 4H),4.83 (s, 2H).

[0386] 2.3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

[0387] The title compound was prepared from 3-chlorobenzylsulfonylchloride (113 mg, 0.5 mmol), as prepared in the preceding step, and3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (120 mg, 0.5mmol), as prepared in step 3 of Example 1, using the procedure in step 4of Example 1, as a white solid (180 mg, 84%). ¹H-NMR (300 MHz, CDCl₃)δ7.37 (d, J=7.6 Hz, 1H), 7.30 (m, 4H), 7.20 (s, 1H), 6.02 (d, J=7.7 Hz,1H), 4.78 (s, 2H), 4.27 (s, 2H), 2.27 (s, 3H), 1.50 (s, 9H).

[0388] 3.3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone

[0389] The title compound was prepared from3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(170 mg, 0.4 mmol), as prepared in the preceding step, using theprocedure in step 5 of Example 1, as an off white solid (150 mg, 100%).¹H-NMR (300 MHz, CDCl₃) δ8.83 (s, 1H), 7.45 (s, 1H), 7.37 (m, 3H), 7.18(d, J=7.5 Hz, 1H), 6.11 (d, J=7.6 Hz, 1H), 4.79 (s, 2H), 4.56 (s, 2H),2.27 (s, 3H).

[0390] 4.3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

[0391] The title compound was prepared from3-(chlorobenzylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone (140mg, 0.38 mmol), as prepared in the preceding step, and[N,N′-di(tert-butoxycarbonyl)] 2-aminoethoxyguanidine (120 mg, 0.38mmol), as prepared in step 4 of Example 2, using the procedure in step 5of Example 2, as a colorless foam (140 mg, 57%). ¹H-NMR (300 MHz, CDCl₃)δ9.20 ( s, 1H), 8.46 (br s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.32 (m,3H), 7.18 (m, 1H), 6.00 (d, J=7.7 Hz, 1H), 4.91 (s, 2H), 4.26 (s, 2H),4.14 (t, J=5.3 Hz, 2H), 3.63 (q, J=5.2 Hz, 2H), 2.31 (s, 3H), 1.52 (s,9H), 1.49 (s, 9H).

[0392] 5.3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0393] The title compound was prepared from3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone (140 mg, 0.22mmol), as prepared in the preceding step, using the procedure in step 6of Example 2, as a white solid (95 mg, 74%). ¹H-NMR (300 MHz, DMSO-d₆)δ11.00 (s, 1H), 8.74 (s, 1H), 8.49 (t, J=5.5 Hz, 1H), 7.74 (br s, 4H),7.45 (s, 1H), 7.40 (m, 3H), 7.18 (d, J=7.5 Hz, 1H), 6.12 (d, J=7.7 Hz,1H), 4.75 (s, 2H), 4.56 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.41 (m, 2H),2.26 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₈H₂₃ClN₆O₅S: 471.1 (M+H), 493.1 (M+Na), 509.1(M+K); Found: 471.2, 493.2, 509.2.

[0394] The following compounds (Example 10 to Example 27 ) were preparedin a manner analogous to Example 9.

EXAMPLE 10

[0395] 3-(3-Trifluoromethylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0396]¹H-NMR (300 MHz, DMSO-d₆) δ10.97 (s, 1H), 8.79 (s, 1H), 8.50 (t,J=4.6 Hz, 1H), 7.74 (br s, 4H), 7.68 (m, 4H), 7.17 (d, J=7.5 Hz, 1H),6.11 (d, J=7.5 Hz, 1H), 4.74 (s, 2H), 4.68 (s, 2H), 3.83 (t, J=5.4 Hz,2H), 3.41 (m, 2H), 2.25 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉H₂₃F₃N₆O₅S: 505.1(M+H), 527.1 (M+Na), 543.1 (M+K); Found: 505.1, 527.1, 543.1.

EXAMPLE 11

[0397]3-(2-Trifluoromethylbenzyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0398]¹H-NMR (300 MHz, DMSO-d₆) δ11.00 (s, 1H), 9.12 (s, 1H), 8.50 (t,J=5.5 Hz, 1H), 7.75 (br s, 4H), 7.68 (m, 3H), 7.57 (m, 1H), 7.24 (d,J=7.6 Hz, 1H), 6.16 (d, J=7.7 Hz, 1H), 4.76 (s, 2H), 4.66 (s, 2H), 3.83(t, J=5.4 Hz, 2H), 3.39 (m, 2H), 2.28 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉H₂₃F₃N₆O₅S: 505.1(M+H), 527.1 (M+Na); Found: 505.1, 527.1.

EXAMPLE 12

[0399] 3-(2-Iodobenzylsulfonyl)amino-6methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0400]¹H-NMR (300 MHz, DMSO-d₆) δ11.06 (s, 1H), 8.90 (s, 1H), 8.51 (t,J=5.5 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.78 (br s, 4H), 7.52 (d, J=7.7Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.6Hz, 1H), 6.15 (d, J=7.7 Hz, 1H), 4.75 (s, 2H), 4.65 (s, 2H), 3.83 (t,J=5.4 Hz, 2H), 3.41 (m, 2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₃IN6O₅S: 563.1(M+H), 585.1 (M+Na); Found: 562.7, 584.7.

EXAMPLE 13

[0401] 3-(2-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0402]¹H-NMR (300 MHz, DMSO-d₆) δ10.95 (s, 1H), 8.90 (s, 1H), 8.50 (t,J=5.5 Hz, 1H), 7.70 (br s, 4H), 7.54 (d, J=7.1 Hz, 1H), 7.48 (d, J=7.5Hz, 1H), 7.36 (t, J=7.3 Hz, 2H), 7.20 (d, J=7.5 Hz, 1H), 6.14 (d, J=7.7Hz, 1H), 4.75 (s, 2H), 4.66 (s, 2H), 3.83 (t, J=5.3 Hz, 2H), 3.41 (m,2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₁₈H₂₃ClN₆O₅S: 471.1 (M+H), 493.1 (M+Na); Found:470.7, 492.7.

EXAMPLE 14

[0403] 3-(2Bromobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0404]¹H-NMR (300 MHz, DMSO-d₆) δ10.99 (s, 1H), 8.91 (s, 1H), 8.50 (t,J=5.6 Hz, 1H), 7.74 (br s, 4H), 7.65 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.6Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.21 (d, J=7.5Hz, 1H), 6.14 (d, J=7.7 Hz, 1H), 4.75 (s, 2H), 4.67 (s, 2H), 3.83 (t,J=5.3 Hz, 2H), 3.41 (m, 2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₃BrN₆O₅S: 515.1(M+H), 537.1 (M+Na); Found: 514.8, 536.7.

EXAMPLE 15

[0405] 3-(3-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0406]¹H-NMR (300 MHz, DMSO-d₆) δ10.92 (s, 1H), 8.73 (s, 1H), 8.49 (t,J=5.4 Hz, 1H), 7.69 (br s, 4H), 7.38 (m, 1H), 7.22 (m, 3H), 7.17 (d,J=7.5 Hz, 1H), 6.12 (d, J=7.7 Hz, 1H), 4.74 (s, 2H), 4.56 (s, 2H), 3.83(t, J=5.3 Hz, 2H), 3.39 (m, 2H), 2.26 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₃FN₆O₅S: 455.2(M+H), 477.1 (M+Na), 493.1 (M+K); Found: 455.3, 477.3, 493.2.

EXAMPLE 16

[0407] 3-(4-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0408]¹H-NMR (300 MHz, DMSO-d₆) δ11.02 (s, 1H), 8.66 (s, 1H), 8.50 (t,J=5.5 Hz, 1H), 7.75 (br s, 4H), 7.39 (s, 4H), 7.16 (d,.J=7.5 Hz, 1H),6.11 (d, J=7.6 Hz, 1H), 4.74 (s, 2H), 4.54 (s, 2H), 3.83 (t, J=5.4 Hz,2H), 3.41 (m, 2H), 2.26 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₃ClN₆O₅S: 471.1(M+H), 493.1 (M+Na); Found: 471.1, 493.1.

EXAMPLE 17

[0409]3-((2-Chloro-6-fluoro)benzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0410]¹H-NMR (300 MHz, DMSO-d₆) δ10.96 (s, 1H), 9.11 (s, 1H), 8.49 (t,J=5.5 Hz, 1H), 7.71 (br s, 4H), 7.45 (dd, J=8.1, 2.1 Hz, 1H), 7.37 (d,J=7.6 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 6.16 (d,J=7.8 Hz, 1H), 4.74 (s, 2H), 4.68 (s, 3.83 (t, J=5.4 Hz, 2H), 3.40 (t,J=5.3 Hz, 2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₂ClFN₆O₅S: 489.1(M+H), 511.1 (M+Na); Found: 488.9, 510.9.

EXAMPLE 18

[0411] 3-(2-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0412]¹H-NMR (300 MHz, DMSO-d₆) δ11.03 (s, 1H), 8.86 (s, 1H), 8.51 (t,J=5.5 Hz, 1H), 7.76 (br s, 4H), 7.47 (m, 2H), 7.20 (m, 3H), 6.13 (d,J=7.7 Hz, 1H), 4.74 (s, 2H), 4.55 (s, 2H), 3.83 (t, J=5.5 Hz, 2H), 3.39(t, J=5.6 Hz, 2H), 2.26 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₃FN₆O₅S: 455.2(M+H), 477.1 (M+Na); Found: 455.0, 477.1.

EXAMPLE 19

[0413] 3-(4-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0414]¹H-NMR (300 MHz, DMSO-d₆) δ11.04 (s, 1H), 8.63 (s, 1H), 8.51 (t,J=5.6 Hz, 1H), 7.76 (br s, 4H), 7.39 (m, 2H), 7.16 (m, 3H), 6.11 (d,J=7.7 Hz, 1H), 4.74 (s, 2H), 4.53 (s, 2H), 3.84, (t, J=5.3 Hz, 2H), 3.41(t, J=5.5 Hz, 2H), 2.25 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₃FN₆O₅S: 455.2(M+H), 477.1 (M+Na); Found: 455.0, 476.9.

EXAMPLE 20

[0415]3-(2,3-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0416]¹H-NMR (300 MHz, DMSO-d₆) δ10.92 (s, 1H), 9.02 (s, 1H), 8.49 (t,J=5.5 Hz, 1H), 7.69 (br s, 4H), 7.64 (d, J=8.0 Hz, 1H), 7.54 (d, J=7.7Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 6.15 (d, J=7.7Hz, 1H), 4.75 (s, 4H), 3.83 (t, J=5.3 Hz, 2H), 3.41 (t, J=5.5 Hz, 2H),2.27 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₈H₂₂Cl₂N₆O₅S: 505.1 (M+H), 527.1 (M+Na); Found:504.8, 527.1.

EXAMPLE 21

[0417]3-(3,4-Difluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0418]¹H-NMR (300 MHz, DMSO-d₆) δ10.99 (s, 1H), 8.77 (s, 1H), 8.49 (t,J=5.5 Hz, 1H), 7.67 (br s, 4H), 7.49 (m, 1H), 7.42 (m, 1H), 7.24 (m,1H), 7.19 (d, J=7.5 Hz, 1H), 6.13 (d, J=7.7 Hz, 1H), 4.74 (s, 2H), 4.54(s, 2H), 3.83 (t, J=5.3 Hz, 2H), 3.39 (t, J=5.4 Hz, 2H), 2.26 (s, 3H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₈H₂₂F₂N₆O₅S: 473.1 (M+H), 495.1 (M+Na); Found: 473.1, 495.1.

EXAMPLE 22

[0419]3-(2,4-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0420]¹H-NMR (300 MHz, DMSO-d₆) δ10.99 (s, 1H), 8.99 (s, 1H), 8.51 (t,J=5.5 Hz, 1H), 7.74 (br s, 4H), 7.66 (s, 1H), 7.58 (d, J=8.4 Hz, 1H),7.44 (d, J=8.3 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 6.15 (d, J=7.9 Hz, 1H),4.75 (s, 2H), 4.66 (s, 2H), 3.83 (t, J=5.3 Hz, 2H), 3.41 (t, J=5.2 Hz,2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₁₈H₂₂Cl₂N₆O₅S: 505.1 (M+H), 527.1 (M+Na);Found: 505.1, 527.1.

EXAMPLE 23

[0421]3-(2,5-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0422]¹H-NMR (300 MHz, DMSO-d₆) δ10.95 (s, 1H), 9.07 (s, 1H), 8.49 (t,J=5.5 Hz, 1H), 7.71 (br s, 4H), 7.66 (s, 1H), 7.52 (d, J=8.5 Hz, 1H),7.45 (d, J=8.6 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 6.15 (d, J=7.8 Hz, 1H),4.76 (s, 2H), 4.67 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.38 (t, J=5.5 Hz,2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₁₈H₂₂Cl₂N₆O₅S: 505.1 (M+H), 527.1 (M+Na);Found: 505,1, 526.9.

EXAMPLE 24

[0423] 3-(3,4-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0424]¹H-NMR (300 MHz, DMSO-d₆) δ10.96 (s, 1H), 8.82 (s, 1H), 8.50 (t,J=5.5 Hz, 1H), 7.72 (br s, 4H), 7.66 (s, 1H), 7.61 (d, J=8.3 Hz, 1H),7.60 (d, J=8.3 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 6.12 (d, J=7.7 Hz, 1H),4.75 (s, 2H), 4.59 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.38 (m, 2H), 2.26(s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₈H₂₂Cl₂N₆O₅S: 505.1 (M+H), 527.1 (M+Na); Found:504.8, 526.8.

EXAMPLE 25

[0425]3-(1-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0426]¹H-NMR (300 MHz, DMSO-d₆) δ11.02 (s, 1H), 8.72 (s, 1H), 8.51 (t,J=5.5 Hz, 1H), 8.20 (m, 1H), 7.93 (m, 1H), 7.75 (br s, 4H), 7.67 (m,1H), 7.53 (m, 4H), 7.16 (d, J=7.5 Hz, J=5.3 Hz, 2H), 2.26 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₂H₂₆N₆O₅S: 487.5 (M+H); Found: 487.8.

EXAMPLE 26

[0427]3-(2-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0428]¹H-NMR (300 MHz, DMSO-d₆) δ11.06 (s, 1H), 8.62 (s, 1H), 8.52 (t,J=5.3 Hz, 1H), 7.86 (m, 4H), 7.78 (br s, 4H), 7.52 (m, 3H), 7.21 (d,J=7.5 Hz, 1H), 6.07 (d, J=7.7 Hz, 1H), 4.74 (s, 2H), 4.69 (s, 2H), 3.85(t, J=5.2 Hz, 2H), 3.43 (t, J=5.3 Hz, 2H), 2.22 (s, 3H). Mass spectrum(LCMS, ESI) calcd. for C₂₂H₂₆N₆O₅S: 487.5 (M+H); Found: 487.1.

EXAMPLE 27

[0429]3-(2-Methylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0430]¹H-NMR (300 MHz, DMSO-d₆) δ11.07 (s, 1H), 8.72 (s, 1H), 8.51 (t,J=5.5 Hz, 1H), 7.78 (br s, 4H), 7.21 (m, 4H), 7.12 (d, J=7.5 Hz, 1H),6.11 (d, J=7.7 Hz, 1H), 4.75 (s, 2H), 4.54 (s, 2H), 3.83 (t, J=5.4 Hz,2H), 3.41 (t, J=5.4 Hz, 2H), 2.34 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₉H₂₆N₆O₅S: 451.3 (M+H); Found: 451.2.

EXAMPLE 28

[0431]3-(3-Chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0432] 1.3-(3-Chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

[0433] To a suspension of3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(190 mg, 0.44 mmol), as prepared in step 2 of Example 9, and potassiumcarbonate (276 mg, 2.0 mmol) in acetonitrile (10 mL) was addediodomethane (142 mg, 1.0 mmol). The mixture was stirred at ambienttemperature overnight. Water (50 mL) was added to the mixture, extractedwith ethyl acetate (3×30 mL). The organic layer was washed with brine(2×30 mL) and dried over Na₂SO₄. The solvent was evaporated to give thetitle compound as a colorless foam (195 mg, 100%). ¹H-NMR (300 MHz,CDCl₃) δ7.51 (s, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.33 (m, 3H), 6.11 (d,J=7.6 Hz, 1H), 4.75 (s, 2H), 4.38 (s, 2H), 3.22 (s, 3H), 2.33 (s, 3H),1.49 (s, 9H).

[0434] 2.3-(3-Chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0435] The title compound was prepared from3-(3-chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone,as prepared in the preceding step, using the procedures in step 5 ofExample 1 and steps 5 and 6 of Example 2, as a white solid. ¹H-NMR (300MHz, DMSO-d₆) δ10.97 (s, 1H), 8.50 (t, J=5.5 Hz, 1H), 7.73 (br s, 4H),7.53 (s, 1H), 7.42 (m, 3H), 7.37 (d, J=7.5 Hz, 1H), 6.12 (d, J=7.5 Hz,1H), 4.76 (s, 2H), 4.53 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.39 (t, J=5.5Hz, 2H), 3.05 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉H₂₅ClN₆O₅S: 485.1(M+H), 507.1 (M+Na); Found: 485.1, 507.1.

EXAMPLE 29

[0436]3-(3,4-Dichlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0437] The title compound was prepared in a manner analogous to Example28. ¹H-NMR (300 MHz, DMSO-d₆) δ10.97 (s, 1H), 8.51 (t, J=5.5 Hz, 1H),7.74 (br s, 5H), 7.66 (d, J=8.2 Hz, 1H), 7.45 (m, 1H), 7.42 (d, J=7.5Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 4.77 (s, 2H), 4.55 (s, 2H), 3.83 (t,J=5.3 Hz, 2H), 3.39 (t, J=5.6 Hz, 2H), 3.05 (s, 3H), 2.32 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₉H₂₄Cl₂N₆O₅S 519.1 (M+H), 541.1 (M+Na); Found: 519.3, 541.4.

EXAMPLE 30

[0438]3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0439] 1.3-(Benzyloxycarbonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone: To asolution of3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(6.0 g, 17 mmol), as prepared in step 2 of Example 1, in methylenechloride (12 mL) was added trifluoroacetic acid (12 mL) and the reactionstirred at ambient temperature. After 30 minutes the reaction wasconcentrated in vacuo, dissolved in methylene chloride, and diluted withhexane. The precipitated product was collected by filtration and driedin vacuo giving a quantitative yield of white solid. ¹H NMR (300 MHz,DMSO-d₆) δ13.17 (br s, 1H), 8.36 (s, 1H), 7.74 (d, 1H, J=7.5 Hz), 7.35(m, 5H), 6.18 (d, 1H, J=7.7 Hz), 5.15 (s, 2H), 4.77 (s, 2H), 2.25 (s,3H).

[0440] 2.3-Benzyloxycarbonylamino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone: To a solution of3-(benzyloxycarbonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone (0.85g, 2.5 mmol), as prepared in the preceding step, and[N,N′-di(tert-butoxycarbonyl)] 3-amino-1-ethoxyguanidine (0.86 g, 2.7mmol), as prepared in step 4 of Example 2, in N,N-dimethylformamide (42mL), was added N,N-diisopropylethylamine (0.59 mL, 3.4 mmol) andCastro's reagent (BOP; 1.31 g, 3.0 mmol). After stirring 2 hours atambient temperature, the reaction was concentrated in vacuo and thecrude product recrystallized from 3:1 ethyl acetate:hexane giving acolorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ9.11 (s, 1H), 8.71 (s, 1H),8.36 (m, 1H), 8.30 (s, 1H), 7.74 (d, 1H, J=7.6 Hz), 7.37 (m, 5H), 6.16(d, 1H, J=8.1 Hz), 5.15 (s, 2H), 4.72 (s, 2H), 3.87 (t, 2H, J=5 Hz),3.39 (m, 2H), 2.81 (d, 2H, J=11 Hz), 2.24 (s, 3H), 1.42 (s, 9H), 1.39(s, 9H).

[0441] 3. 3-Amino-6-methyl-1-{([N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone: To a solution of3-benzyloxycarbonylamino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone (0.80 g, 1.3 mmol),as prepared in the preceding step, in 2:1 ethanol:tetrahydrofuran (96mL) was added 10% palladium (0) on activated carbon (64 mg). Afterdegassing and backfilling with nitrogen, the reaction was stirred underhydrogen gas at atmospheric pressure for 1 hour, filtered throughCelite, and the filtrate concentrated in vacuo giving a colorless solidthat was used without further purification.

[0442] 4.3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone: To a solution of3-amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl) aminocarbonyl]}-2-pyridinone (0.11 g, 0.23 mmol),as prepared in the preceding step, in methylene chloride (4 mL) wasadded 2-chlorobenzenesulfonyl chloride (0.048 g, 0.23 mmol) andN-methylmorpholine (0.024 mL, 0.22 mmol). After stirring 4 hours atambient temperature, the reaction was diluted with additional methylenechloride and washed with saturated aqueous NaHCO₃, 10% aqueous citricacid, and brine. The organic layer was then separated and evaporated invacuo and the crude product used without further purification.

[0443] 5.3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate:3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone, as prepared in thepreceding step, was dissolved in methylene chloride (ca. 4 mL) andtreated with neat trifluoroacetic acid (ca. 2 mL) at ambient temperaturefor 4 hours. After evaporation, the crude product was dissolved inmethylene chloride, washed with saturated aqueous NaHCO₃, 10% aqueouscitric acid, and brine, dried over Na₂SO₄, filtered and evaporated. Thecrude product was then purified on a Waters silica Sep-Pak (gradientelution: 10-50% ethyl acetate in methylene chloride) giving the titlecompound (0.11 g, 89%). ¹H NMR (300 MHz, DMSO-d₆) δ10.97 (s, 1H), 9.21(s, 1H), 8.45 (t, 1H, J=5.6 Hz), 8.01 (m, 1H), 7.73 (br s, 4H), 7.64 (m,2H), 7.49 (m, 1H), 7.21 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=7.9 Hz), 4.64(s, 2H), 3.80 (t, 2H, J=5.3 Hz), 3.40 (m, 2H), 2.19 (s, 3). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₇H₂₁N₆O₅SCl: 479.1 (M+Na), 457.1 (M+H). Found: 479.4, 457.3.

EXAMPLE 31

[0444] 3-(4-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0445] The title compound was prepared as in Example 30 starting with4-chlorobenzenesulfonyl chloride (0.048 g, 0.23 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.94 (s, 1H), 9.50 (s, 1H), 8.41 (t, 1H, J=5.6 Hz), 7.80 (m,2H), 7.69 (br s, 4H), 7.60 (m, 2H), 7.28 (d, 1H, J=7.6 Hz), 6.11 (d, 1H,J=7.7 Hz), 4.60 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.39 (m, 2H), 2.20 (s,3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₇H₂₁N₆O₅SCl: 479.1 (M+Na), 457.1 (M+H). Found: 479.4,457.0.

EXAMPLE 32

[0446] 3-(Phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0447] The title compound was prepared as in Example 30 starting withbenzenesulfonyl chloride (0.030 mL, 0.23 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ11.00 (s, 1H), 9.34 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.82 (m,2H), 7.75 (br s, 4H), 7.60 (m, 3H), 7.26 (d, 1H, J=7.6 Hz), 6.09 (d, 1H,J=7.6 Hz), 4.61 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.38 (m, 2H), 2.19 (s,3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₇H₂₁N₆O₅SCl: 445.1 (M+Na), 423.1 (M+H). Found: 445.1,423.0.

EXAMPLE 33

[0448] 3-(3-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0449] The title compound was prepared as in Example 30 starting with3-chlorobenzenesulfonyl chloride (0.048 g, 0.23 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ11.14 (br s, 1H), 9.63 (s, 1H), 8.45 (br s, 1H), 7.77 (m, 6H),7.55 (t, 1H, J=7.9 Hz), 7.29 (d, 1H, J=7.6 Hz), 6.11 (d, 1H, J=7.7 Hz),4.61 (s, 2H), 3.79 (t, 2H, J=3.39 (m, 2H), 2.20 (s, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₇H₂₁N₆O₅SCl: 479.1 (M+Na), 457.1 (M+H). Found: 479.0, 457.0.

EXAMPLE 34

[0450]3-(2-Methylsulfonylphenyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0451] The title compound was prepared in a manner analogous to Example30. ¹H-NMR (300 MHz, DMSO-d₆) δ8.32 (t, J=5.5 Hz, 1H), 8.21 (d, J=7.6Hz, 1H), 8.13 (d, J=7.5 Hz, H), 7.92 (m, 2H), 7.43 (d, J=7.4 Hz, 1H),6.21 (br s, 4H), 6.12 (d, J=7.5 Hz, 1H), 4.58 (s, 2H), 3.68 (t, J=5.4Hz, 2H), 3.47 (s, 3H), 3.29 (t, 2H, J=5.6 Hz), 2.17 (s, 3). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₂₄N₆O₅S₂: 501.1 (M+H), 523.1 (M+Na), 539.1 (M+K); Found: 501.1,523.3, 539.4.

EXAMPLE 35

[0452] 3-(2-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0453] 1.3-(2-Naphthalenylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone: To a solution of3-amino-6-methyl-1- {[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl) aminocarbonyl]}-2-pyridinone (0.050 g, 0.10mmol), as prepared in step 3 of Example 30, in methylene chloride (2 mL)was added 2-naphthalenesulfonyl chloride (0.023 g, 0.10 mmol) anddiethylaminomethyl-polystyrene resin (0.033 g, ca. 0.10 mmol). Afterstirring 5 hours at ambient temperature, aminomethylated polystyreneresin (0.10 g, ca. 0.20 mmol) and more methylene chloride (2 mL) wereadded and the reaction was stirred an additional 16 hours. The resultingsuspension was poured onto a Waters silica Sep-Pak and eluted with10-50% ethyl acetate in methylene chloride, and the eluted productconcentrated in vacuo and used directly in the next step.

[0454] 2.3-(2-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate: The product of thepreceding step was dissolved in methylene chloride (ca. 2 mL) andtreated with neat trifluoroacetc acid (ca. 1 mL) at ambient temperaturefor 4 hours. After evaporation, the crude product was purified on aWaters silica Sep-Pak with 5% methanol in methylene chloride giving thetitle compound (0.007 g, 12%). ¹H NMR (300 MHz, DMSO-d₆) δ8.42 (m, 1H),7.98 (m, 3H), 7.78 (dd, 1H, J=8.7 Hz, 1.9 Hz), 7.63 (m, 2H), 7.55 (d,1H, J=7.6 Hz), 6.19 (dd, 1H, J=7.7 Hz, 0.8 Hz), 4.64 (s, 2H), 3.83 (t,2H, J=5 Hz), 3.42 (t, 2H, J=5 Hz), 2.26 (s, 3), Mass spectrum (LCMS,ESI) calcd. for C₁₇H₂₁N₆O₅SCl: 473.3 (M+H). Found: 473.2.

EXAMPLE 36

[0455] 3-(4-Bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0456] The title compound was prepared as in Example 35 starting with4-bromobenzenesulfonyl chloride (0.026 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.90 (s, 1H), 9.51 (s, 1H), 8.41 (t, 1H, J=5.6 Hz), 7.71 (m,8H), 7.28 (d, 1H, J=7.5 Hz), 6.11 (d, 1H, J=7.7 Hz), 4.60 (s, 2H), 4.11(m, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.40 (m, 2H), 2.20 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₇H₂₁N₆O₅SBr: 503.0 (M+H). Found:503.0.

EXAMPLE 37

[0457] 3-(4-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0458] The title compound was prepared as in Example 35 starting with4-fluorobenzenesulfonyl chloride (0.020 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.90 (s, 1H), 9.41 (s, 1H), 8.41 (t, 1H, J=5.7 Hz), 7.87 (m,2H), 7.68 (br s, 4H), 7.36 (m, 2H), 7.28 (d, 1H, J=7.5 Hz), 6.10 (d, 1H,J=7.7 Hz), 4.60 (s, 2H), 4.10 (brd s, 2H), 3.79 (t, 2H, 5.3 Hz), 3.41(m, 2H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₇H₂₁N₆O₅SF: 441.2 (M+H). Found: 441.2.

EXAMPLE 38

[0459] 3-(4-Iodophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0460] The title compound was prepared as in Example 35 starting with4-iodobenzenesulfonyl chloride (0.030 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.95 (s, 1H), 9.48 (s, 1H), 8.42 (t, 1H, J=5.6 Hz), 7.91 (d,2H, J=8.6 Hz), 7.72 (br s, 4H), 7.56 (d, 2H, J=8.6 Hz), 7.27 (d, 1H,J=7.6 Hz), 6.10 (d, 1H, J=7.7 Hz), 4.60 (s, 2H), 3.80 (t, 2H, J=5.3 Hz),3.39 (m, 2H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₇H₂₁N₆O₅SI: 549.1 (M+H). Found: 549.0.

EXAMPLE 39

[0461]3-(4-Methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0462] The title compound was prepared as in Example 35 starting with4-methoxybenzenesulfonyl chloride (0.021 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.93 (s, 1H), 9.11 (s, 1H), 8.42 (m, IH), 7.77 (d, 2H, J=9.0Hz), 7.67 (m, 4H), 7.24 (d, 1H, J=7.5 Hz), 7.04 (d, 2H, J=8.9 Hz), 6.08(d, 1H, J=8.0 Hz), 4.61 (s, 2H), 3.79 (m, 5H), 3.40 (m, 2H), 2.19 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈H₂₄N₆O₆S: 453.3 (M+H).Found: 453.2.

EXAMPLE 40

[0463] 3-(4-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0464] The title compound was prepared as in Example 35 starting with4-methylbenzenesulfonyl chloride (0.021 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.93 (s, 1H), 9.21 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.70 (m,6H), 7.33 (d, 2H, J=8.2 Hz), 7.24 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=7.8Hz), 4.61 (s, 2H), 4.10 (m, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.41 (m, 2H),2.35 (s, 3H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₈H₂₄N₆O₅S: 437.3 (M+H). Found: 437.2.

EXAMPLE 41

[0465]3-(3-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0466] The title compound was prepared as in Example 35 starting with3-(trifluoromethyl)benzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.86 (s, 1H), 9.76 (s, 1H), 8.40 (t, 1H, J=5.5 Hz),8.15 (s, 1H), 8.09 (d, 1H, J=8.0 Hz), 8.01 (d, 1H, J=7.9 Hz), 7.76 (t,1H, J=7.9 Hz), 7.67 (br s, 4H), 7.32 (d, 1H, J=7.5 Hz), 6.12 (d, 1H,J=7.7 Hz), 4.59 (s, 2H), 3.78 (t, 2H, J=5.3 Hz), 3.39 (m, 2H), 2.20 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈H₂₁N₆O₅SF₃: 491.2 (M+H).Found: 491.1.

EXAMPLE 42

[0467]3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl]aminocarbonylmethyl)-2-pyridinone trifluoroacetate

[0468] The title compound was prepared as in Example 35 starting with3,4-dichlorobenzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹H NMR (300MHz, DMSO-d₆) δ10.90 (s, 1H), 9.73 (s, 1H), 8.41 (t, 1H, J=5.5 Hz), 8.05(d, 1H, J=2.1 Hz), 7.80 (d, 1H, J=8.4 Hz), 7.70 (m, 5H), 7.32 (d, 1H,J=7.5 Hz), 6.13 (d, 1H, J=7.7 Hz), 4.60 (s, 2H), 3.79 (t, 2H, J=5.3 Hz),3.40 (m, 2H), 2.21 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₇H₂₀N6O₅SCl₂: 491.2 (M+H). Found: 491.2.

EXAMPLE 43

[0469]3-(3-Chloro-4-fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0470] The title compound was prepared as in Example 35 starting with3-chloro-4-fluorobenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.86 (s, 1H), 9.64 (s, 1H), 8.40 (t, 1H, J=5.6 Hz),8.05 (dd, 1H, J=6.9 Hz, 2.3 Hz), 7.79 (ddd, 1H, J=8.7 Hz, 4.5 Hz, 2.3Hz), 7.65 (brd s, 4H), 7.57 (t, 1H, J=8.9 Hz), 7.31 (d, 1H, J=7.5 Hz),6.12 (d, 1H, J=7.6 Hz), 4.60 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.40 (m,2H), 2.21 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇H₂₀N₆O₅SFCl:475.2 (M+H). Found: 475.2.

EXAMPLE 44

[0471]3-(4-Isopropylphenylsufonyl)amino-6-methyl-1-[(2-guanidinooxethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0472] The title compound was prepared as in Example 35 starting with4-isopropylbenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹H NMR (300MHz, DMSO-d₆) δ10.87 (s, 1H), 9.25 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.77(d, 2H, J=8.4 Hz), 7.66 (br s, 4H), 7.41 (d, 2H, J=8.4 Hz), 7.25 (d, 1H,J=7.6 Hz), 6.09 (d, 1H, J=7.7 Hz), 4.62 (s, 2H), 3.79 (t, 2H, J=5.3 Hz),3.39 (m, 2H), 2.95 (p, 1H, J=6.9 Hz), 2.21 (s, 3H), 1.19 (d, 6H, J=6.9Hz). Mass spectrum (LCMS, ESI) calcd. for C₂₀H₂₈N₆O₅S: 465.3 (M+H).Found: 465.2.

EXAMPLE 45

[0473] 3-(3-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0474] The title compound was prepared as in Example 35 starting with3-fluorobenzenesulfonyl chloride (0.020 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.86 (s, 1H), 9.58 (s, 1H), 8.41 (t, 1H, J=5.5 Hz), 7.59 (m,8H), 7.9 (d, 1H, J=7.6 Hz), 6.11 (d, 1H, J=7.6 Hz), 4.61 (s, 2H), 3.79(t, 2H, J=5.3 Hz), 3.41 (m, 2H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₇H₂₁N₆O₅SF: 441.2 (M+H). Found: 441.1.

EXAMPLE 46

[0475]3-(3,5-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0476] The title compound was prepared as in Example 35 starting with3,5-dichlorobenzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹H NMR (300MHz, DMSO-d₆) δ0.86 (s, 1H), 9.85 (s, 1H), 8.41 (t, 1H, J=5.5 Hz), 7.93(t, 1H, J=1.8 Hz), 7.83 (d, 2H, J=1.8 Hz), 7.66 (br s, 4H), 7.33 (d, 1H,J=7.6 Hz), 6.14 (d, 1H, J=7.6 Hz), 4.62 (s, 2H), 3.79 (t, 2H, J=5.3 Hz),3.40 (m, 2H), 2.22 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₇H₂₀N₆O₅SCl₂: 491.2 (M+H). Found: 491.2.

EXAMPLE 47

[0477]3-(3,4-Dimethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0478] The title compound was prepared as in Example 35 starting with3,4-dimethoxybenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR (300MHz, DMSO-d₆) δ10.84 (s, 1H), 9.13 (s, 1H), 8.42 (t, 1H, J=5.6 Hz), 7.65(br s, 4H), 7.41 (m, 2H), 7.26 (d, 1H, J=7.5 Hz), 7.05 (d, 1H, J=9.1Hz), 6.09 (d, 1H, J=7.9 Hz), 4.62 (s, 2H), 3.79 (m, 9H), 3.40 (m, 2H),2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₉H₂₆N₆O₇S: 483.3(M+H). Found: 483.1.

EXAMPLE 48

[0479] 3-(2-Thienylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0480] The title compound was prepared as in Example 35 starting with2-thiophenesulfonyl chloride (0.020 g, 0.11 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.90 (s, 1H), 9.48 (s, 1H), 8.44 (t, 1H, J=5.4 Hz), 7.90 (dd,1H, J=5.0 Hz, 1.3 Hz), 7.69 (br s, 4H), 7.61 (dd, 1H, J=3.8 Hz, 1.3 Hz),7.33 (d, 1H, J=7.6 Hz), 7.12 (dd, 1H, J=4.9 Hz, 3.8 Hz), 6.14 (d, 1H,J=7.7 Hz), 4.63 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.37 (m, 2H), 2.22 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₅H₂₀N₆O₅S₂: 429.6 (M+H).Found: 429.1.

EXAMPLE 49

[0481] 3-(1-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0482] The title compound was prepared as in Example 35 starting with1-naphthalenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.89 (s, 1H), 9.73 (s, 1H), 8.74 (m, 1H), 8.40 (t, 1H, J=5.6Hz), 8.21 (m, 2H), 8.08 (m, 1H), 7.67 (m, 7H), 7.18 (d, 1H, J=7.5Hz),6.04 (d, 1H, J=8.0 Hz), 4.55 (s, 2H), 3.77 (t, 2H, J=5.3 Hz), 3.32 (m,2H), 2.15 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₂₁H₂₄N₆O₅S:473.6 (M+H). Found: 473.2.

EXAMPLE 50

[0483]3-(2,4,6-Trimethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0484] The title compound was prepared as in Example 35 starting with2-mesitylenesulfonyl chloride (0.021 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.93 (s, 1H), 8.94 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.71 (brds, 4H), 7.12 (d, 1H, J=7.5 Hz), 6.99 (s, 2H), 6.07 (d, 1H, J=7.7 Hz),4.60 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.35 (q, 2H, J=5.2 Hz), 2.55 (s,6H), 2.23 (s, 3H), 2.18 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₂₀H₂₈N₆O₅S: 465.6 (M+H). Found: 465.2.

EXAMPLE 51

[0485] 3-(2-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0486] The title compound was prepared as in Example 35 starting witho-toluenesulfonyl chloride (0.019 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.89 (s, 1H), 9.27 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.81 (dd,1H, J=7.9 Hz, 1.2 Hz), 7.70 (m, 4H), 7.49 (td, 1H, J=7.5 Hz, 1.3 Hz),7.34 (dd, 2H, J=11 Hz, 8 Hz), 7.19 (d, 1H, J=7.5 Hz), 6.06 (d, 1H, J=7.7Hz), 4.61 (s, 2H), 3.79 (t, 2H, J=5.2 Hz), 3.36 (m, 2H), 2.61 (s, 3H),2.18 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈H₂₁N₆O₅S: 437.6(M+H). Found: 437.1.

EXAMPLE 52

[0487] 3-(2,5-Dimethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0488] The title compound was prepared as in Example 35 starting withp-xylene-2-sulfonyl chloride (0.022 g, 0.11 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.92 (s, 1H), 9.19 (s, 1H), 8.45 (t, 1H, J=5.4 Hz), 7.68 (m,5H), 7.24 (m, 3H), 6.07 (d, 1H, J=7.6 Hz), 4.63 (s, 2H), 3.80 (t, 2H,J=5.2 Hz), 3.37 (m, 2H), 2.54 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₉H₂₆N₆O₅S: 451.6 (M+H). Found: 451.1.

EXAMPLE 53

[0489] 3-(2-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0490] The title compound was prepared as in Example 35 starting with2-fluorobenzenesulfonyl chloride (0.020 g, 0.10 mmol). ¹H NMR (300 MHz,CD₃OD) δ7.85 (t, 1H, J=7.5 Hz), 7.63 (m, 1H), 7.43 (d, 1H, J=7.7 Hz),7.27 (m, 2H), 6.17 (d, 1H, J=7.7 Hz), 4.70 (s, 2H), 3.94 (t, 2H, J=5.0Hz), 3.49 (t, 2H, J=5.0 Hz), 2.29 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₇H₂₁N₆O₅SF: 441.5 (M+H). Found: 441.1.

EXAMPLE 54

[0491]3-(2-Chloro-6methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0492] The title compound was prepared as in Example 35 starting with2-chloro-6-methylbenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.98 (s, 1H), 9.05 (s, 1H), 8.44 (t, 1H, J=5.4 Hz),7.74 (br s, 4H), 7.46 (m, 2H), 7.34 (m, 1H), 7.20 (d, 1H, J=7.5 Hz),6.09 (d, 1H, J=7.8 Hz), 4.62 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.36 (m,2H), 2.63 (s, 3H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₈H₂₃N₆O₅SCl: 471.0 (M+H). Found: 471.1.

EXAMPLE 55

[0493]3-(3-Bromo-6-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0494] The title compound was prepared as in Example 35 starting with5-bromo-2-methoxybenzenesulfonyl chloride (0.029 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.88 (s, 1H), 8.67 (s, 1H), 8.45 (t, 1H, J=5.6 Hz),7.79 (m, 2H), 7.68 (br s, 4H), 7.24 (d, 1H, J=7.5 Hz), 7.16 (d, 1H,J=8.9 Hz), 6.10 (d, 1H, J=7.8 Hz), 4.65 (s, 2H), 3.80 (m, 5H), 3.37 (m,2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈H₂₃N₆O₆SBr:533.0 (M+H). Found: 533.0.

EXAMPLE 56

[0495] 3-(3-Chloro-2-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0496] The title compound was prepared as in Example 35 starting with3-chloro-2-methylbenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.89 (s, 1H), 9.65 (s, 1H), 8.43 (t, 1H, J=5.5 Hz),7.81 (dd, 1H, J=7.9 Hz, 0.8 Hz), 7.69 (m, 5H), 7.33 (t, 1H, J=8.0 Hz),7.23 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=7.7 Hz), 4.61 (s, 2H), 3.80 (t,2H, J=5.3 Hz), 3.36 (m, 2H), 2.65 (s, 3H), 2.19 (s, 3H). Mass spectrum(LCMS, ESI) calcd. for C₁₈H₂₃N₆O₅SCl: 471.0 (M+H). Found: 471.1.

EXAMPLE 57

[0497]3-(2-Chloro-5-trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0498] The title compound was prepared as in Example 35 starting with2-chloro-5-(trifluoromethyl)benzenesulfonyl chloride (0.027 g, 0.10mmol). ¹H NMR (300 MHz, DMSO-d₆) δ10.89 (s, 1H), 9.90 (s, 1H), 8.43 (t,1H, J=5.5 Hz), 8.31 (d, 1H, J=1.8 Hz), 8.01 (dd, 1H, J=8.5 Hz, 2.0 Hz),7.90 (d, 1H, J=8.3 Hz), 7.69 (br s, 4H), 7.32 (d, 1H, J=7.6 Hz), 6.13(d, 1H, J=7.8 Hz), 4.64 (s, 2H), 3.79 (t, 2H, J=5.4 Hz), 3.35 (m, 2H),2.22 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈H₂₀N₆O₅SClF₃:525.0 (M+H). Found: 525.1.

EXAMPLE 58

[0499]3-(2,4-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0500] The title compound was prepared as in Example 35 starting with2,4-dichlorobenzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹H NMR (300MHz, DMSO-d₆) δ10.89 (s, 1H), 9.46 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.96(d, 1H, J=8.6 Hz), 7.86 (d, 1H, J=2.1 Hz), 7.69 (br s, 4H), 7.57 (dd,1H, J=8.6 Hz, 2.1 Hz), 7.23 (d, 1H, J=7.6 Hz), 6.10 (d, 1H, J=7.7 Hz),4.62 (s, 2H), 3.80 (t, 2H, J=5.2 Hz), 3.37 (m, 2H), 2.21 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₇H₂₀N₆O₅SCl₂: 491.4 (M). Found: 491.1.

EXAMPLE 59

[0501] 3-(4-Vinylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0502] The tide compound was prepared as in Example 35 starting withp-styrenesulfonyl chloride (0.021 g, 0.11 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.92 (s, 1H), 9.34 (s, 1H), 8.42 (t, 1H, J=5.4 Hz), 7.79 (d,2H, J=8.4 Hz), 7.71 (br s, 4H), 7.62 (d, 2H, J=8.4 Hz), 7.26 (d, 1H,J=7.6 Hz), 6.78 (dd, 1H, J=17.7 Hz, 11.0 Hz), 6.09 (d, 1H, J=7.7 Hz),5.99 (d, 1H, J=17.6 Hz), 5.44 (d, 1H, J=11.1 Hz), 4.60 (s, 2H), 3.78 (t,2H, J=5.2 Hz), 3.35 (m, 2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₉H₂₄N₆O₅S: 449.6 (M+H). Found: 449.2.

EXAMPLE 60

[0503]3-(2-Butoxy-5-(1,1-dimethylpropyl)phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0504] The title compound was prepared as in Example 35 starting with2-(n-butoxy)-5-(2′-isopentyl)benzenesulfonyl chloride (0.033 g, 0.10mmol). ¹H NMR (300 MHz, DMSO-d₆) δ10.88 (brd s, 1H), 8.44 (br s, 1H),8.11 (s, 1H), 7.68 (m, 5H), 7.53 (dd, 1H, J 8.7 Hz, 2.4 Hz), 7.16 (d,1H, J=7.6 Hz), 7.10 (d, 1H, J=8.8 Hz), 6.03 (d, 1H, J=4.66 (s, 2H), 4.01(t, 2H, J=6.4 Hz), 3.80 (t, 2H, J=5.2 Hz), 3.39 (m, 2H), 2.14 (s, 3H),1.76 (m, 2H), 1.57 (m, 2H), 1.47 (m, 2H), 1.22 (s, 6H), 0.94 (t, 3H,J=7.4 Hz), 0.55 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI) calcd. forC₂₆H₄₀N₆O₆S: 565.8 (M+H). Found: 565.2.

EXAMPLE 61

[0505] 3-(3-Nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0506] The title compound was prepared as in Example 35 starting with3-nitrobenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.81 (br s, 1H), 9.85 (br s, 1H), 8.56 (t, 1H, J=1.9 Hz),8.43 (dd, 1H, J=8.3 Hz, 1.4 Hz), 8.34 (m, 1H), 8.18 (d, 1H, J=8.2 Hz),7.81 (t, 1H, J=8.0 Hz), 7.60 (br s, 4H), 7.34 (d, 1H, J=7.6 Hz), 6.13(d, 1H, J=7.7 Hz), 4.55 (s, 2H), 3.77 (m, 2H), 3.38 (m, 2H), 2.20 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇H₂₁N₇O₇S: 468.2 (M+H).Found: 469.2.

EXAMPLE 62

[0507]3-(4-Chloro-3-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0508] The title compound was prepared as in Example 35 starting with4-chloro-3-nitrobenzenesulfonyl chloride (0.026 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.90 (br s, 1H), 9.92 (br s, 1H), 8.44 (d, 1H,J=2.1 Hz), 8.38 (t, 1H, J=5.6 Hz), 8.02 (dd, 1H, J=8.5 Hz, 2.1 Hz), 7.92(d, 1H, J=8.5 Hz), 7.68 (br s, 4H), 7.36 (d, 1H, J=7.5 Hz), 6.15 (d, 1H,J=7.9 Hz), 4.58 (br s, 2H), 3.79 (t, 2H, J=5.4 Hz), 3.38 (m, 2H), 2.22(s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇H₂₀N₇O₇SCl: 502.0(M+H). Found: 502.1.

EXAMPLE 63

[0509]3-(4-Methylcarbonylaminophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0510] The title compound was prepared as in Example 35 starting with4-(acetylamino)benzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.86 (br s, 1H), 10.32 (s, 1H), 9.13 (s, 1H), 8.41(t, 1H, J=5.5 Hz), 7.76 (d, 2H, J=8.9 Hz), 7.69 (d, 2H, J=9.0 Hz), 7.63(br s, 4H), 7.23 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=8.1 Hz), 4.61 (s,2H), 3.79 (t, 2H, J=5.4 Hz), 3.39 (m, 2H), 2.19 (s, 3H), 2.07 (s, 3H).Mass spectrum (LCMS, ESI) calcd. for C₁₉H₂₅N₇O₆S: 480.2 (M+H). Found:480.2.

EXAMPLE 64

[0511]3-(4-tert-Butylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0512] The title compound was prepared as in Example 35 starting with4-(tert-butyl)benzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR (300MHz, DMSO-d₆) δ10.85 (s, 1H), 9.27 (s, 1H), 8.43 (t, 1H, J=5.4 Hz), 7.79(d, 2H, 8.5 Hz), 7.65 (br s, 4H), 7.56 (d, 2H, J=8.6 Hz), 7.25 (d, 1H,J=7.6 Hz), 6.09 (d, 1H, J=7.9 Hz), 4.62 (s, 2H), 3.79 (t, 2H, J=5.3 Hz),3.40 (m, 2H), 2.19 (s, 3H), 1.28 (s, 9H). Mass spectrum (LCMS, ESI)calcd. for C₂₁H₃₀N₆O₅S: 479.3 (M+H). Found: 479.2.

EXAMPLE 65

[0513]3-(4-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0514] The title compound was prepared as in Example 35 starting with4-(trifluoromethyl)benzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.92 (s, 1H), 9.73 (s, 1H), 8.40 (t, 1H, J=5.5 Hz),8.01 (d, 2H, J=8.2 Hz), 7.91 (d, 2H, J=8.5 Hz), 7.69 (br s, 4H), 7.31(d, 1H, J=7.5 Hz), 6.12 (d, 1H, J=8.0 Hz), 4.59 (s, 2H), 3.78 (t, 2H,J=5.3 Hz), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₈H₂₁N₆O₅SF₃: 491.2 (M+H). Found: 491.2.

EXAMPLE 66

[0515] 3-(3- Cyanophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0516] The title compound was prepared as in Example 35 starting with3-cyanobenzenesulfonyl chloride (0.020 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.91 (br s, 1H), 9.73 (br s, 1H), 8.40 (t, 1H, J=5.6 Hz),8.27 (t, 1H, J=1.6 Hz), 8.09 (dd, 1H, J=7.9 Hz, 1.6 Hz), 7.72 (m, 5H),7.33 (d, 1H, J=7.5 Hz), 6.12 (d, 1H, J=7.6 Hz), 4.59 (s, 2H), 4.10 (brs, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.38 (m, 2H), 2.21 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₈H₂₁N₇O₅S: 448.2 (M+H). Found: 449.2.

EXAMPLE 67

[0517]3-(4-Methylsulfonylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0518] The title compound was prepared as in Example 35 starting with4-(methylsulfonyl)benzenesulfonyl chloride (0.024 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.87 (s, 1H), 9.78 (s, 1H), 8.40 (t, 1H, J=5.4 Hz),8.06 (s, 4H), 7.66 (br s, 4H), 7.32 (d, 1H, J=7.5 Hz), 6.12 (d, 1H,J=7.8 Hz), 4.59 (s, 2H), 3.78 (t, 2H, J=5.2 Hz), 3.40 (m, 2H), 3.28 (s,3H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈H₂₄N₆O₇S₂:501.2 (M+H). Found: 501.1.

EXAMPLE 68

[0519] 3-Dansylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0520] The title compound was prepared as in Example 35 starting withdansyl chloride (0.027 g, 0.10 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ10.98(s, 1H), 9.66 (s, 1H), 8.39 (m, 3H), 8.20 (d, 1H, J=7.3 Hz), 7.75 (br s,4H), 7.58 (m, 2H), 7.25 (d, 1H, J=7.6 Hz), 7.16 (d, 1H, J=7.6 Hz), 6.04(d, 1H, J=7.7 Hz), 4.59 (s, 2H), 3.79 (t, 2H, J=5.1 Hz), 3.35 (m, 2H),2.82 (s, 6H), 2.15 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₂₃H₂₉N7O₅S: 516.7 (M+H). Found: 516.2.

EXAMPLE 69

[0521]3-(Pentafluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0522] The title compound was prepared as in Example 35 starting withpentafluorobenzenesulfonyl chloride (0.028 g, 0.11 mmol). ¹H NMR (300MHz, CD₃OD) δ7.55 (d, 1H, J=7.6 Hz), 6.27 (d, 1H, J=7.6 Hz), 4.68 (s,2H), 3.94 (t, 2H, J=5.0 Hz), 3.48 (t, 2H, J=5.0 Hz), 2.33 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₆H₁₇N₆O₅SF₅: 513.5 (M+H). Found:513.1.

EXAMPLE 70

[0523]3-(2,5-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0524] The title compound was prepared as in Example 35 starting with2,5-dichlorobenzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹H NMR (300MHz, DMSO-d₆) δ10.89 (s, 1H), 9.68 (s, 1H), 8.44 (t, 1H, J=5.5 Hz), 8.03(d, 1H, J=2.1 Hz), 7.70 (m, 6H), 7.29 (d, 1H, J=7.6 Hz), 6.13 (d, 1H,J=7.9 Hz), 4.65 (s, 2H), 3.80 (t, 2H, J=5.2 Hz), 3.39 (m, 2H), 2.22 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇H₂₀N₆O₅SCl₂: 491.0 (M+H).Found: 491.1.

EXAMPLE 71

[0525] 3-(2-Nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0526] The title compound was prepared as in Example 35 starting with2-nitrobenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR (300 MHz,CD₃OD) δ8.00 (dd, 1H, J=7.6 Hz, 1.7 Hz), 7.91 (dd, 1H, J=7.8 Hz, 1.4Hz), 7.77 (m, 2H), 7.59 (d, 1H, J=7.6 Hz), 6.26 (dd, 1H, J=7.7 Hz, 0.8Hz), 4.70 (s, 2H), 3.92 (t, 2H, J=5.2 Hz), 3.48 (t, 2H, J=5.2 Hz), 2.31(s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇H₂₁N₇O₇S: 468.5 (M+H).Found: 468.1.

EXAMPLE 72

[0527]3-Di(4-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0528] The title compound was prepared as in Example 35 starting with4-nitrobenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ11.17 (s, 1H), 8.43 (d, 4H, J=8.9 Hz), 8.12 (d, 4H, J=8.9 Hz),7.84 (m, 4H), 7.60 (d, 1H, J=7.6 Hz), 6.34 (d, 1H, J=7.8 Hz), 4.63 (s,2H), 3.82 (m, 2H), 3.38 (m, 2H), 2.29 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₂₃H₂₄N₈O₁₁S₂: 653.6 (M+H). Found: 653.1.

EXAMPLE 73

[0529]3-(2,5-Dimethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0530] The title compound was prepared as in Example 35 starting with2,5-dimethoxybenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR (300MHz, CD₃OD) δ7.38 (d, 1H, J=7.7 Hz), 7.35 (d, 1H, J=2.8 Hz), 7.12 (dd,1H, J=9.0 Hz, 2.8 Hz), 7.04 (d, 1H, J=9.0 Hz), 6.13 (d, 1H, J=7.7 Hz),4.73 (s, 2H), 3.95 (t, 2H, J=5.0 Hz), 3.83 (s, 3H), 3.76 (s, 3H), 3.50(t, 2H, J=5.1 Hz), 2.26 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₉H₂₆N₆O₇S: 483.6 (M+H). Found: 483.1.

EXAMPLE 74

[0531] 3-(4-Propylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0532] The title compound was prepared as in Example 35 starting with4-n-propylbenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹H NMR (300MHz, CD₃OD) δ7.70 (m, 2H), 7.47 (d, 1H, J=7.6 Hz), 7.30 (d, 2H, J=7.9Hz), 6.19 (d, 1H, J=7.7 Hz), 4.70 (s, 2H), 3.93 (t, 2H, J=5.0 Hz), 3.48(t, 2H, J=5.0 Hz), 2.63 (t, 2H, J=7.6 Hz), 2.29 (s, 3H), 1.63 (sextet,2H, J=7.5 Hz), 0.92 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI) calcd.for C₂₀H₂₈N₆O₅S: 465.6 (M+H). Found: 465.2.

EXAMPLE 75

[0533]3-(2-Methyl-5-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0534] The title compound was prepared as in Example 35 starting with2-methyl-5-nitrobenzenesulfonyl chloride (0.024 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ11.04 (s, 1H), 9.87 (s, 1H), 8.45 (d, 1H, J=2.5 Hz),8.38 (t, 1H, J=5.5 Hz), 8.30 (dd, 1H, J=8.4 Hz, 2.5 Hz), 7.77 (br s,4H), 7.65 (d, 1H, J=8.5 Hz), 7.32 (d, 1H, J=7.5 Hz), 6.12 (d, 1H, J=7.6Hz), 4.55 (s, 2H), 3.78 (t, 2H, J=5.3 Hz), 3.32 (m, 2H), 2.75 (s, 3H),2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈H₂₃N₇O₇S: 482.5(M+H). Found: 482.1.

EXAMPLE 76

[0535]3-(2-trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0536] The title compound was prepared as in Example 35 starting with2-(trifluoromethyl)benzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.95 (s, 1H), 9.50 (s, 1H), 8.45 (t, 1H, J=5.4 Hz),8.15 (m, 1H), 7.98 (m, 1H), 7.80 (m, 2H), 7.73 (br s,4H), 7.28 (d, 1H,J=7.6 Hz), 6.12 (d, 1H, J=7.7 Hz), 4.63 (s, 2H), 3.80 (t, 2H, J=5.2 Hz),3.36 (m, 2H), 2.21 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₈H₂₁N₆O₅SF₃: 491.5 (M+H). Found: 491.1.

EXAMPLE 77

[0537]3-(2,3-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0538] The title compound was prepared as in Example 35 starting with2,3-dichlorobenzenesulfonyl chloride (0.023 g, 0.09 mmol). ¹H NMR (300MHz, DMSO-d₆) δ11.02 (s, 1H), 9.58 (s, 1H), 8.45 (t, 1H, J=5.5 Hz), 7.97(dd, 1H, J=8.0 Hz, 1.3 Hz), 7.91 (dd, 1H, J=8.1 Hz, 1.3 Hz), 7.77 (br s,4H), 7.50 (t, 1H, J=8.0 Hz), 7.24 (d, 1H, J=7.5 Hz), 6.10 (d, 1H, J=7.7Hz), 4.63 (s, 2H), 3.80 (t, 2H, J=5.2 Hz), 3.36 (m, 2H), 2.21 (s, 3H).Mass spectrum (LCMS, ESI) calcd. for C₁₇H₂₀N₆O₅SCl ₂: 491.0 (M+H).Found: 491.1.

EXAMPLE 78

[0539]3-(2-Trifluoromethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0540] The title compound was prepared as in Example 35 starting with2-(trifluoromethoxy)benzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹HNMR (300 MHz, DMSO-d₆) δ10.93 (s, 1H), 9.31 (s, 1H), 8.44 (t, 1H, J=5.5Hz), 7.98 (dd, 1H, J=7.9 Hz, 1.6 Hz), 7.75 (m, 5H), 7.51 (m, 2H), 7.26(d, 1H, J=7.5 Hz), 6.11 (d, 1H, J=7.7 Hz), 4.63 (s, 2H), 3.80 (t, 2H,J=5.3 Hz), 3.36 (m, 2H), 2.21 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₁₈H₂₁N₆O₆SF₃: 507.5 (M+H). Found: 507.1.

EXAMPLE 79

[0541] 3-(4-(3-Chloro-2-cyanophenoxy)phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0542] The title compound was prepared as in Example 35 starting with4-(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride (0.032 g, 0.10mmol). ¹H NMR (300 MHz, DMSO-d₆) δ10.95 (s, 1H), 9.43 (s, 1H), 8.43 (t,1H, J=5.3 Hz), 7.89 (d, 2H, J=8.7 Hz), 7.72 (m, 5H), 7.57 (d, 1H, J=8.1Hz), 7.30 (m, 3H), 7.11 (d, 1H, J=8.4 Hz), 6.11 (d, 1H, J=7.7 Hz), 4.61(s, 2H), 3.79 (t, 2H, J=5.0 Hz), 3.34 (m, 2H), 2.20 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₄H₂₄N₇O₆SCl: 574.0 (M+H). Found: 574.1.

EXAMPLE 80

[0543]3-(2-Chloro-4-fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0544] The title compound was prepared as in Example 35 starting with2-chloro-4-fluorobenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.92 (m, 1H), 9.34 (s, 1H), 8.44 (t, 1H, J=5.5 Hz),8.04 (dd, 1H, J=8.9 Hz, 5.9 Hz), 7.69 (m, 5H), 7.36 (m, 1H), 7.23 (d,1H, J=7.6 Hz), 6.10 (d, 1H, J=7.7 Hz), 7.7 Hz), 4.63 (s, 2H), 3.80 (t,2H, J=5.0 Hz), 3.37 (m, 2H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₇H₂₀N₆O₅SClF: 475.0 (M+H). Found: 475.1.

EXAMPLE 81

[0545]3-(5-Chloro-2-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0546] The title compound was prepared as in Example 35 starting with5-chloro-2-methoxybenzenesulfonyl chloride (0.025 g, 0.11 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.89 (s, 1H), 8.67 (s, 1H), 8.44 (t, 1H, J=5.4 Hz),7.68 (m, 6H), 7.23 (m, 2H), 6.10 (d, 1H, J=7.8 Hz), 4.65 (s, 2H), 3.79(m, 5H), 3.38 (m, 2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₁₈H₂₃N₆O₆SCl: 487.0 (M+H). Found: 487.1.

EXAMPLE 82

[0547]3-(2-Methoxy-5-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0548] The title compound was prepared as in Example 35 starting with2-methoxy-5-methylbenzenesulfonyl chloride (0.023 g, 0.11 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.88 (s, 1H), 8.45 (t, 1H, J=5.5 Hz), 8.29 (s, 1H),7.68 (br s, 4H), 7.58 (d, 1H, J=1.9 Hz), 7.40 (dd, 1H, J=8.5 Hz, 1.9Hz), 7.20 (d, 1H, J=7.6 Hz), 7.07 (d, 1H, J=8.5 Hz), 7.16 (d, 1H, J=8.9Hz), 6.07 (d, 1H, J=7.7 Hz), 4.65 (s, 2H), 3.80 (m, 5H), 3.39 (m, 2H),2.27 (s, 3H), 2.17 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₉H₂₆N₆O₆S: 467.6 (M+H). Found: 467.1.

EXAMPLE 83

[0549] 3-(4-Phenylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0550] The title compound was prepared as in Example 35 starting with4-phenylbenzenesulfonyl chloride (0.026 g, 0.10 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ10.90 (s, 1H), 9.41 (s, 1H), 8.42 (t, 1H, J=5.4 Hz), 7.91 (d,2H, J=8.5 Hz), 7.83 (d, 2H, J=8.5 Hz), 7.71 (m, 6H), 7.46 (m, 3H), 7.31(d, 1H, J=7.6 Hz), 6.11 (d, 1H, J=7.7 Hz), 4.61 (s, 2H), 3.76 (t, 2H,J=5.0 Hz), 3.37 (m, 2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₂₃H₂₆N₆O₅S: 499.6 (M+H). Found: 499.2.

EXAMPLE 84

[0551]3-(5-Chlorothiophene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0552] The title compound was prepared as in Example 35 starting with5-chlorothiophene-2-sulfonyl chloride (0.023 g, 0.11 mmol). ¹H NMR (300MHz, DMSO-d₆) δ10.93 (s, 1H), 9.76 (s, 1H), 8.44 (t, 1H, J=5.5 Hz), 7.67(br s, 4H), 7.46 (d, 1H, J=4.1 Hz), 7.34 (d, 1H, J=7.5 Hz), 7.18 (d, 1H,J=4.1 Hz), 6.16 (d, 1H, J=7.7 Hz), 4.64 (s, 2H), 3.80 (t, 2H, J=5.2 Hz),3.38 (m, 2H), 2.24 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₅H₁₉N₆O₅S₂Cl: 463.0 (M+H). Found: 463.1.

EXAMPLE 85

[0553]3-(6-Chloronaphthalene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0554] The title compound was prepared as in Example 35 starting with2-(6-chloro)naphthalenesulfonyl chloride (0.026 g, 0.10 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.87 (s, 1H), 9.53 (s, 1H), 8.53 (s, 1H), 8.38 (t,1H, J=5.5 Hz), 8.17 (m, 2H), 8.05 (d, 1H, J=8.8 Hz), 7.91 (dd, 1H, J=8.7Hz, 1.8 Hz), 7.68 (m, 5H), 7.32 (d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.9Hz), 4.56 (s, 2H), 3.76 (t, 2H, J=5.2 Hz), 3.36 (m, 2H), 2.17 (s, 3H).Mass spectrum (LCMS, ESI) calcd. for C₂₁H₂₃N₆O₅SCl: 507.0 (M+H). Found:507.1.

EXAMPLE 86

[0555]3-(6-Bromonaphthalene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0556] The title compound was prepared as in Example 35 starting with2-(6-bromo)naphthalenesulfonyl chloride (0.033 g, 0.11 mmol). ¹H NMR(300 MHz, DMSO-d₆) δ10.85 (s, 1H), 9.53 (s, 1H), 8.52 (s, 1H), 8.38 (t,1H, J=5.4 Hz), 8.33 (s, 1H), 8.11 (d, 1H, J=8.8 Hz), 8.04 (d, 1H, J=8.8Hz), 7.90 (dd, 1H, J=8.7 Hz, 1.6 Hz), 7.79 (dd, 1H, J=8.8 Hz, 1.8 Hz),7.66 (br s, 4H), 7.32 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=7.7 Hz), 4.56(s, 2H), 3.76 (t, 2H, J=5.2 Hz), 3.39 (m, 2H), 2.17 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₁H₂₃N₆O₅SBr: 553.0 (M+H). Found:553.0.

EXAMPLE 87

[0557] 3-(3-Bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0558] The title compound was prepared as in Example 2 starting with3-bromobenzenesulfonyl chloride (0.128 g, 0.501 mmol). ¹H-NMR (300 MHz,CD₃OD) δ7.98 (t, 1H, J=1.8 Hz), 7.75 (m, 2H), 7.50 (d, 1H, J=7.6 Hz),7.40 (t, 1H, J=8.0 Hz), 6.22 (d, 1H, J=7.6 Hz), 4.69 (s, 2H), 3.93 (t,2H, J=5.2 Hz), 3.49 (t, 2H, J=5.2 Hz), 2.31 (s, 3H). Mass spectrum(LCMS, ESI) calcd. for C₁₇H₂₀N₆O₅SBr: 501.5 (M+H). Found: 501.3.

EXAMPLE 88

[0559] 3-(Quinoline-8-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethylaminiocarbonylmethyl]-2-pyridinone trifluoroacetate

[0560] The title compound was prepared in a manner analogous to Example30. ¹H-NMR (300 Hz, CD₃OD) δ9.06−9.05 (m, 1H), 8.40−8.37 (m, 2H), 8.16(d, J=7.0 Hz, 1H), 7.68−7.59 (m, 3H), 6.06 (d, J=7.6 Hz, 1H), 4.57 (s,2H), 3.71 (t, J=10.5 Hz, 2H), 3.34−3.33 (m, 2H), 2.17 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₀H₂₃SO₅N₇: 474.4 (M+H); Found: 474.3.

EXAMPLE 89

[0561] 3-(Quinoline-5-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0562] The title compound was prepared in a manner analogous to Example30. ¹H-NMR (300 Hz, CD₃OD) δ9.32 (br s, 1H), 8.62−8.30 (m, 4H),7.73−7.70 (m, 1H), 7.28 (br s, 1H), 6.12 (d, J=6.6 Hz, 1H), 4.62 (s,2H), 3.64 (br s, 2H), 3.37 (br s, 2H), 2.23 (s, 3H) Mass spectrum (LCMS,ESI) calcd. for C₂₀H₂₃SO₅N₇: 474.4 (M+H); Found: 474.3.

EXAMPLE 90

[0563]3-(1-Methylimidazole-4-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0564] The title compound was prepared in a manner analogous to Example30. ¹H-NMR (300 Hz, CD₃OD) δ7.73 (br s, 2H), 7.36 (d, 1H), 6.37−6.35(m,2H), 4.89 (s, 2H), 4.89 (s, 2H), 3.86 (bs, 2H), 3.43 (br s, 2H), 3.34(s, 3H), 2.34 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₅H₂₂SO₅N₈:427.4 (M+H); Found 427.4.

EXAMPLE 91

[0565]3-(3-Methylquinoline-8-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0566] The title compound was prepared in a manner analogous to Example30. ¹H-NMR (300 Hz, CD₃OD) δ8.89 (d, J=2.2 Hz, 1H), 8.30 (dd, J=1.3, 7.3Hz, 1H), 8.17−8.16 (m, 1H), 8.10 (dd, J=1.3, 7.0 Hz, 1H), 7.62 (t, J=7.4Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.09 (d, J=7.1 Hz, 1H), 4.59 (s, 2H),3.90 (t, J=5.1 Hz, 2H), 2.55 (s, 3H), 2.19 (S, 3H). Mass spectrum (LCMS,ESI) calcd. for C₂₁H₂₆SO₅N₇: 488.5 (M+H); Found 488.5.

EXAMPLE 92

[0567] 3-(2-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0568] 1.3-(2-Pyridinylsulfonyl)amino-6-methyl-1-[[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl])-2-pyridinone

[0569] To a stirred reaction mixture of 2-mercaptopyridine (500 mg, 4.5mmol) and 1N HCl (5 mL) at 0° C., was bubbled in chlorine gas for 1 hr.The reaction mixture was extracted with methylene chloride (3×50 mL),dried (Na₂SO₄), and concentrated to yield a clear oil, which was usedimmediately. N,N-Dimethylaminopyridine (200 mg) is added to a stirredreaction mixture of 2-pyridinesulfonyl chloride (50 mg, 0.178 mmol), and3-amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][3-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone (78 mg, 0.162 mmol),as prepared in step 3 of Example 30, in methylene chloride (2 mL).Reaction mixture was stirred 16 hrs, concentrated in vacuo and purifiedon silica gel column chromatrography (4% methanol/96% methylenechloride) to give the title compound as a white solid (34 mg, 30%yield). Mass spectrum (LCMS, ESI) calcd. for C₂₆H₃₇SO₉N₇: 624.6 (M+H);Found 624.1.

[0570] 2. 3-(2-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0571] To a stirred reaction mixture of3-(2-pyridinylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone (34 mg, 0.055mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (0.5mL). The reaction was stirred at ambient temperature for 2 hr, and waspurified on a Waters Sep-Pak (2g) (10% methanol/89% methylene chloride,1% trifluoroacetic acid), to yield the title compound as a yellow solid(9 mg, 39% yield). ¹H-NMR (300 Hz, CD₃OD) δ8.92 (s, 1H), 8.70 (br s,1H), 8.15 (d, J=8.0 Hz, 1H), 7.57−7.49 (m, 2H), 6.23 (d, J=7.6 Hz, 1H),4.67 (s, 1H), 3.91 (t, J=5.0 Hz, 2H), 3.47 (t, J=5.0 Hz, 2H), 2.30 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₆H₂₁SO₅N₇: 424.4 (M+H);Found 424.1.

EXAMPLE 93

[0572] 3-(3-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0573] The title compound was prepared in a manner analogous to Example92. ¹H-NMR (300 Hz, CD₃OD) δ8.92 (br s, 1H), 8.70 (br s, 1H), 8.16 (d,J=8.0 Hz, 1H), 7.57−7.49 (m, 2H), 6.23 (d, J=7.6 Hz, 1H), 4.67 (s, 2H),3.9 (t, J=5.0 Hz, 2H), 3.47 (t, J=5.0 Hz, 2H), 2.30 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₆H₂₁SO₅N₇: 424.4 (M+H); Found 424.1.

EXAMPLE 94

[0574] 3-(4-Ethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0575] The title compound was prepared as in Example 2 starting with4-ethylbenzenesulfonyl chloride (0.102 g, 0.498 mmol). ¹H NMR (300 MHz,CD₃OD) δ7.71 (d, 2H, J=8.4 Hz), 7.47 (d, 1H, J=7.6 Hz), 7.31 (d, 2H,J=8.4 Hz), 6.19 (dd, 1H, J=7.7 Hz, 0.5 Hz), 4.71 (s, 2H), 3.93 (t, 2H,J=5.1 Hz), 3.48 (t, 2H, J=5.1 Hz), 2.68 (q, 2H, J=7.6 Hz), 2.29 (s, 3H),1.22 (t, 3H, J=7.6 Hz). Mass spectrum (LCMS, ESI) calcd. forC₁₉H₂₅N₆O₅S: 450.5 (M+H). Found: 451.2.

EXAMPLE 95

[0576]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)-N-methylaminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0577] The title compound was prepared from 2-(methylamino)ethanol usingthe procedures in steps 6-10 of Example 1 and steps 5 & 6 of Example 2.¹H-NMR (300 Hz, CD₃OD) δ7.65 (m, 2H), 7.35 (m, 2H), 6.16 (m, 1H),5.04−5.01 (m, 2H), 3.97−3.92 (m, 2H), 3.69−3.63 (m, 2H) 3.29 (s, 3H),2.36 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₉H₂₆SO₅N₆: 451.4(M+H); Found: 451.4.

EXAMPLE 96

[0578]3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone hydrochloride

[0579] 1. 3-Cyano-6-isopropyl-2(1H)-pyridinone: A solution of3-cyano-6-methyl-2(1H)-pyridinone (10.0 g, 74.6 mmol) in anhydroustetrahydrofuran (100 mL) was cooled to −78° C. under nitrogen andreacted slowly with lithium diisopropylamide solution (40 mL of 1.4 Mand 85 mL of 2.0 M, 226 mmol total) via syringe. After warming to 0° C.and stirring 2 hours, methyl iodide (10 mL, 160 mmol) was added and thereaction stirred 18 hours at ambient temperature. The reaction waspoured into 0.67 N NaOH (300 mL), the phases separated, the aqueouslayer washed with diethyl ether, and the combined organic layersextracted with water. The combined aqueous layers were acidified to pH 4with 6 N HCl and extracted with methylene chloride, and the methylenechloride layer was washed with brine, dried over Na₂SO₄, and filtered.The filtrate was concentrated in vacuo and the residue purified by flashcolumn chromatography (1:1 methylene chloride: ethyl acetate) giving thetitle compound as a light yellow solid (2.15 g, 18%). ¹H NMR (300 MHz,CDCl₃) δ13.25 (br s, 1H), 7.84 (d, 1H, J=7.5 Hz), 6.23 (d, 1H, J=7.5Hz), 3.00 (septet, 1H, J=7.0 Hz), 1.36 (s, 3H), 1.34 (s, 3H). Alsorecovered from the column was the mono-methylated side-product3-cyano-6-ethyl-2(1H)pyridinone (5.50 g, 50%). which was used to makethe title compound in Example 97. ¹H NMR (300 MHz, CDCl₃) δ7.84 (d,J=7.5, Hz, 1H), 6.23 (d, J=7.4 Hz, 1H), 2.76 (q, J=7.6 Hz, 2H), 1.35 (t,J=7.5 Hz, 3H).

[0580] 2. 3-Carboxy-6-isopropyl-2(1H)-pyridinone:3-Cyano-6-isopropyl-2(1H)-pyridinone (2.92 g, 18.0 mmol), as prepared inthe preceding step, was dissolved in hot 50% v/v sulfuric acid (45 mL)and refluxed for 3 hours. After cooling to ambient temperature, thereaction mixture was poured into 200 mL of ice water and the resultingprecipitate collected by filtration, washed with water, then air andvacuum dried giving the title compound (2.83 g, 87%) as a white solid.¹H NMR (300 MHz, CDCl₃) δ13.67 (s, 1H), 12.75 (br s, 1H), 8.56 (d, 1H,J=7.5 Hz), 6.56 (dd, 1H, J=7.6 Hz, 1.6 Hz), 3.02 (septet, 1H, J=6.9 Hz),1.41 (s, 3H), 1.39 (s, 3H).

[0581] 3. 3-(Benzyloxycarbonyl)amino-6-isopropyl-2(1H)-pyridinone:3-Carboxy-6-isopropyl-2(1H)-pyridinone (2.82 g, 15.6 mmol), as preparedin the preceding step, diphenylphosphoryl azide (3.50 mL, 16.2 mmol),and triethylamine (2.30 mL, 16.5 mmol) were refluxed in 1,4-dioxane (100mL) for 16 hours. Benzyl alcohol (1.65 mL, 15.9 mmol) and additionaltriethylamine (2.40 mL, 17.2 mmol) were added and the reaction refluxedanother 24 hours. After concentrating the reaction mixture in vacuo, theresidue was dissolved in methylene chloride, washed with pH 1 brine,saturated NaHCO₃, and pH 7 brine, dried over MgSO₄, and filtered. Theevaporated filtrate was then purified by flash column chromatography(gradient elution, 10% to 25% ethyl acetate in methylene chloride)giving the title compound as a light yellow solid (1.10 g, 25%). ¹H NMR(300 MHz, CDCl₃) δ11.61 (br s, 1H), 8.05 (br d, 1H, J=7.2 Hz), 7.67 (s,1H), 7.39 (m, 5H), 6.08 (d, 1H, J=7.7 Hz), 5.21 (s, 2H), 2.80 (septet,1H, J=6.9 Hz), 1.28 (s, 3H), 1.26 (s, 3H).

[0582] 4.3-(Benzyloxycarbonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone:3-(Benzyloxycarbonyl)amino-6-isopropyl-2(1H)-pyridinone (1.10 g, 3.84mmol), as prepared in the preceding step, was dissolved in anhydroustetrahydrofuran (30 mL) and cooled to 0° C. under nitrogen. A 1.0 Msolution of lithium bis(trimethylsilyl)amide in hexanes (4.2 mL, 4.2mmol) was added via syringe and the reaction stirred for one hour.tert-Butylbromoacetate (0.70 mL, 4.3 mmol) was then added via syringeand the reaction stirred at ambient temperature for 16 hours. Afterconcentration in vacuo, the crude product was purified by flash columnchromatography (1:1 hexane:ethyl acetate) giving the title compound as apale yellow oil (1.38 g, 90%). ¹H NMR (300 MHz, CDCl₃) δ8.00 (br d, 1H,J=7.8 Hz), 7.78 (s, 1H), 7.36 (m, 5H), 6.15 (d, 1H, J=7.9 Hz), 5.19 (s,2H), 4.79 (s, 2H), 2.72 (m, 1H), 1.46 (s, 9H), 1.26 (s, 3H), 1.23 (s,3H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. forC₂₂H₂₈N₂O₅: 423.2 (M+Na). Found: 423.6.

[0583] 5.3-Amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone:3-(Benzyloxycarbonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(1.35, 3.37 mmol), as prepared in the preceding step, and 10% palladium(0) on activated carbon (0.12 g) were dissolved in methanol (50 mL),degassed, backfilled with nitrogen, and stirred under hydrogen gas atambient pressure and temperature for 2 hours. The reaction mixture wasthen filtered through Celite and the filtrate evaporated giving thetitle compound as a golden oil, which was used without furtherpurification.

[0584] 6.3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone:3-Amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (assumedto be 3.37 mmol), as prepared in the preceding step, andN-methylmorpholine (1.0 mL, 9.1 mmol) were dissolved in methylenechloride (20 mL) and cooled to 0° C. A solution of m-toluenesulfonylchloride (0.67 g, 3.5 mmol) in methylene chloride (5 mL) was added andthe reaction stirred at ambient temperature for 16 hours. Afterevaporation in vacuo, the crude product was dissolved in methylenechloride, washed with 10% aqueous citric acid, saturated NaHCO₃, andbrine, dried over MgSO₄, and filtered. The evaporated filtrate gave thetitle compound (1.24 g, 88%) as a tan solid. ¹H NMR (300 MHz, CDCl₃)δ7.65 (m, 2H), 7.58 (br s, 1H), 7.46 (d, 1H, J=7.8 Hz), 7.33 (m, 2H),6.08 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 2.67 (m, 1H), 2.38 (s, 3H), 1.41(s, 9H), 1.22 (s, 3H), 1.19 (s, 3H).

[0585] 7.3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(carboxymethyl)-2-pyridinone:3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(1.24 g, 2.95 mmol), as prepared in the preceding step, was dissolved inmethylene chloride (20 mL) and reacted with trifluoroacetic acid (8 mL)at ambient temperature for 2 hours. After evaporation in vacuo, thecrude product was dissolved in methylene chloride, washed with pH 7buffer and brine, dried over MgSO₄, and filtered. Evaporation of thefiltrate gave the title compound (0.72 g, 67%) as a light yellow solid.Mass spectrum (LCMS, ESI) calcd. for C₁₇H₂₀N₂O₅S: 365.4 (M+H). Found:365.1.

[0586] 8.3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-{[N,N′-di(tert-butoxycarbonyl)]-2-(guanidinyloxyethyl)aminocabonylmethyl}-2-pyridinone:3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(carboxymethyl)-2-pyridinone(0.71 g, 1.95 mmol), as prepared in the preceding step, Castro's reagent(BOP, 0.905 g, 2.05 mmol), and [N,N′-di(tert-butoxycarbonyl)]2-aminoethoxyguanidine (0.710 g, 2.00 mmol), as prepared in step 4 ofExample 2, were dissolved in methylene chloride (40 mL) and reacted withtriethylamine (6.75 mL, 5.4 mmol) at ambient temperature for 3 days.After concentration in vacuo, the crude product was dissolved inmethylene chloride, washed with 10% aqueous citric acid, saturatedNaHCO₃, and brine, dried over Na₂SO₄, and filtered. The evaporatedfiltrate was purified by flash column chromatography (5% methanol inmethylene chloride) giving the title compound as a light yellow solid(0.70 g, 54%). ¹H NMR (300 MHz, CDCl₃) δ9.15 (s, 1H), 8.34 (br t, 1H,J=5.0 Hz), 7.67 (m, 3H), 7.59 (s, 1H), 7.40 (d, 1H, J=7.9 Hz), 7.34 (m,2H), 6.06 (d, 1H, J=7.9 Hz), 4.86 (s, 2H), 4.09 (m, 2H), 3.58 (dd, 2H,J=8.8 Hz, 5.0 Hz), 2.86 (m, 1H), 2.38 (s, 3H), 1.52 (s, 9H), 1.47 (s,9H), 1.20 (s, 3H), 1.17 (s, 3H).

[0587] 9.3-(3-Methylphenylsulfonyl)amino-6-isopropyl1-{2-(guanidinyloxyethyl)aminocabonylmethyl}-2-pyridinonehydrochloride:3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-{[N,N′-di(tert-butoxycarbonyl)]-2-(guanidinyloxyethyl)aminocabonylmethyl}-2-pyridinone(0.70 g, 1.05 mmol), as prepared in the preceding step, was dissolved inmethylene chloride (10 mL) and reacted with trifluoroacetic acid (5 mL)at ambient temperature for 2.5 hours. The evaporated crude product waslyophilized from acetonitrile/water, purified by flash columnchromatography (gradient elution, 10% to 20% methanol in methylenechloride saturated with gaseous ammonia), and evaporated from 4 N HCl inethanol (20 mL) giving the title compound as a white solid (0.36 g,68%). ¹H NMR (300 MHz, DMSO-d₆) δ10.91 (br s, 1H), 9.34 (brd s, 1H),8.49 (t, 1H, J=5.5 Hz), 7.65 (m, 6H), 7.43 (m, 2H), 7.28 (d, 1H, J=7.8Hz), 6.14 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.38(m, 2H), 2.79 (m, 1H), 2.35 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₀H₂₈N₆O₅S: 465.5 (M+H). Found: 465.1.

EXAMPLE 97

[0588]3-(3-Methylphenylsulfonyl)amino-6-ethyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0589] The title compound was prepared in a manner analogous to Example96. ¹H-NMR (300 MHz, DMSO-d₆) δ10.92 (s, 1H), 9.32 (s, 1H), 8.42 (t,J=5.6 Hz, 1H), 7.71 (br s, 4H), 7.67 (s, 1H), 7.64 (t, J=3.0 Hz, 1H),7.42 (d, J=6.1 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 6.07 (d, J=7.8 Hz, 1H),4.62 (s, 2H), 3.79 (t, J=5.4 Hz, 2H), 3.34 (t, J=5.6 Hz, 2H), 2.24 (s,3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₉H₂₆N₆O₅S: 451.2 (M+H), 473.2 (M+Na); Found: 451.1, 473.0.

EXAMPLE 98

[0590]3-(3-Methylphenylsulfonyl)amino-6-propyl-1-{2-(guanidinyloxyethyl)aminocabonylmethyl}-2-pyridinone trifluoroacetate

[0591] The title compound was prepared in a manner analogous to Example96. ¹H NMR (300MHz, DMSO-d₆) δ11.25 (s, 1H), 9.32 (s, 1H), 8.48 (t, 1H,J=5.5 Hz), 7.91 (br s, 4H), 7.63 (m, 2H), 7.42 (m, 2H), 7.29 (d, 1H,J=7.7 Hz), 6.07 (d, 1H, J=7.7 Hz), 4.61 (s, 2H), 3.81 (t, 2H, J=5.3 Hz),3.35 (m, 2H), 2.45 (t, 2H, J=7.7 Hz), 2.35 (s, 3H), 1.50 (sextet, 2H,J=7.5 Hz), 0.89 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI) calcd. forC₂₀H₂₈N₆O₅S: 465.5 (M+H). Found: 465.1.

EXAMPLE 99

[0592]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride

[0593] A solution of3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone hydrochloride (0.2 g, 0.42 mmol), asprepared in step 5 of Example 5, in N,N-dimethylformamide (6 mL) wastreated with sodium bicarbonate (0.78 g, 9.2 mmol) followed by methyliodide (0.32 mL, 5 mmol) and allowed to stir at room temperature for 2.5h. The reaction mixture was evaporated under high vacuum and the residuewas treated with brine and adjusted to pH 1 with 1M HCl. The insolublematerial was collected by filtration. The aqueous layer was extractedwith methylene chloride (5×). The combined methylene chloride extractswere extracted with saturated sodium bicarbonate (2×). The combinedaqueous bicarbonate extracts were adjusted to pH 1 with 1M HCl. Theinsoluble material was collected by filtration and combined with theprevious solids from the acidic brine treatment. The solids were driedunder high vacuum overnight, then treated with methanol and filtered toremove insoluables. Evaporation of the filtrate gave the title compoundas a white solid (154 mg, 75%). ¹H-NMR (300 MHz, DMSO-d₆) δ9.30 (s, 1H),8.85 (t, J=5.3 Hz, 1H), 8.14 (s, 4H), 7.61-7.66 (m, 2H), 7.39-7.44 (m,2H), 7.23 (d, J=7.6 Hz, 1H), 6.08 (d, J=8.2 Hz, 1H), 4.67 (m, 2H), 3.91(t, J=5.1 Hz, 2H), 3.39 (m, 2H), 3.28 (s, 3H), 2.35 (s, 3H), 2.19 (s,3H). Mass spectrum (LCMS, ESI) clacd. for C₁₉H₂₆N₆O₅S: 451 (M+H); Found:451.2. MS-MS of 451.2 peak gave 408.9 (M-C(═NH)NH).

EXAMPLE 100

[0594]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-ethylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride

[0595] The title compound was prepared in a manner analogous to Example99. ¹H NMR (300 MHz, DMSO-d₆) δ9.26 (br s, 1H), 8.55 (t, 1H, J=5.2 Hz),7.95 (br s, 4H), 7.64 (m, 2H), 7.42 (m, 2H), 7.24 (d, 1H, J=7.5 Hz),6.08 (d, 1H, J=7.7 Hz), 4.63 (s, 2H), 3.87 (br t, 2H, J=5.0 Hz), 3.66(q, 2H, J=6.9 Hz), 2.35 (s, 3H), 2.19 (s, 3H), 1.09 (t, 3H, J=6.9 Hz).Mass spectrum (LCMS, ESI) calcd. for C₂₀H₂₈N₆O₅S: 465.5 (M+H). Found:465.1. MS-MS of 465.1 peak gave 423.0 (M-C(═NH)NH).

EXAMPLE 101

[0596]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-benzylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride

[0597] The title compound was prepared in a manner analogous to Example99. Mass spectrum (LCMS, ESI) calcd. for C₂₅H₃₀N₆O₅S: 527.6 (M+H).Found: 527.0. MS-MS of 527.0 peak gave 485.0 (M-C(═NH)NH).

EXAMPLE 102

[0598]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-butylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride

[0599] The title compound was prepared in a manner analogous to Example99. ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ7.64 (m, 2H), 7.42 (d, 1H, J=7.7 Hz),7.36 (m, 2H), 6.11 (d, 1H, J=7.7 Hz), 4.70 (s, 2H), 3.58 (t, 2H, J=7.3Hz), 3.49 (t, 2H, J=4.9 Hz), 2.39 (s, 3H), 2.30 (s, 3H), 1.64 (m, 2H),1.36 (m, 4H), 0.95 (t, 3H, J=7.2 Hz). Mass spectrum (LCMS, ESI) calcd.for C₂₂H₃₂N₆O₅S: 493.6 (M+H). Found: 493.3. MS-MS of 493.3 peak gave452.0 (M-C(═NH)NH).

EXAMPLE 103

[0600]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0601] 1. [N,N′-Di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)ethoxy-N-methylguanidine

[0602] To a solution of [N,N′-di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino) ethoxyguanidine (905 mg, 2.0 mmol), asprepared in step 3 of Example 2, methanol (121 μL, 3.0 mmol) andtriphenylphosphine (790 mg, 3.0 mmol) in tetrahydrofuran (30 mL) wasadded diethyl azodicarboxylate (520 mg, 3.0 mmol). The mixture wasstirred at ambient temperature overnight. Ethyl acetate (50 mL) wasadded, washed with saturated NaHCO₃ (40 mL), brine (2×40 mL) and driedover Na₂SO₄. After evaporating the solvent, the residue was purified byflash chromatography (0-4% ethyl acetate in methylene chloride) to givethe title compound as a white solid (385 mg, 41%). ¹H-NMR (300 MHz,CDCl₃) δ7.36 (m, 5H), 5.30 (br s, 1H), 5.11 (s, 2H), 4.12 (t, J=5.0 Hz,2H), 3.50 (t, J=5.0 Hz, 2H), 3.07 (s, 3H), 1.48 (s, 9H), 1.43 (s, 9H).

[0603] 2. [N,N′-Di(tert-butoxycarbonyl)] 2-aminoethoxy-N-methylguanidine

[0604] A mixture of [N,N′-di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)ethoxy-N-methylguanidine (700 mg, 1.5 mmol),as prepared in the preceding step, 10% Pd/C (70 mg) in methanol (20 mL)and chloroform (5 mL) was hydrogenated under hydrogen (balloon) for 1 h.The catalyst was removed by filtration through Celite, the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatography(95:5 methylene chloride:methanol saturated with ammonia) to give thetitle compound as a colorless foam (250 mg, 50%). ¹H-NMR (300 MHz,CDCl₃) δ4.14 (t, J=5.0 Hz, 2H), 3.09 (s, 3H), 3.06 (q, J=5.0 Hz, 2H),1.50 (s, 9H), 1.46 (s, 9H).

[0605] 3.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-{[N,N′-di(tert-butoxycarbonyl)][2-(N-methylguanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

[0606] To a solution of3-(3-methylphenylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone(253 mg, 0.75 mmol), as prepared in step 2 of Example 5,[N,N′-di(tert-butoxycarbonyl)] 2-aminoethoxy-N-methylguanidine (250 mg,0.75 mmol), as prepared in the preceding step, diisopropylethylamine(180 μL, 1.0 mmol) in N,N-dimethylformamide (10 ml) was added Castro'sreagent (BOP) (355 mg, 0.8 mmol). The mixture was stirred at roomtemperature overnight. Ethyl acetate (50 mL) was added, washed withsaturated NaHCO₃ (2×20 mL), 10% citric acid (2×20 mL) and brine (20 mL),and dried over Na₂SO₄. After evaporating the solvent in vacuo, theresidue was purified twice by column chromatography (2:1 ethylacetate:hexane; then 2% methanol in methylene chloride) to give thetitle compound as a white solid (380 mg, 78%). ¹H-NMR (300 MHz, CDCl₃)δ8.12 (s, 1H), 7.67 (m, 3H), 7.48 (d, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.31(s, 1H), 7.09 (mn, 1H), 6.08 (d, J=7.8 Hz, 1H), 4.61 (s, 2H), 4.02 (t,J=5.1 Hz, 2H), 3.46 (q, J=5.3 Hz, 2H), 3.09 (s, 2.39 (s, 3H), 2.37 (s,3H), 1.53 (s, 9H), 1.47 (s, 9H).

[0607] 4.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

[0608] A mixture of3-(3-methylphenylsulfonyl)amino-6-methyl-1-([N,N′-di(tert-butoxycarbonyl)][2-(N-methylguanidinooxypropyl)aminocarbonylmethyl])-2-pyridinone (370mg, 0.57 mmol), as prepared in the preceding step, and trifluoroaceticacid (2 mL) in methylene chloride (3 mL) was stirred at room temperaturefor 2 h. After evaporating the solvent in vacuo, the residue waspurified by Waters Sep-Pak (10 g, 10% methanol in methylene chloride) togive the title compound as a colorless foam (310 mg, 96%). ¹H-NMR (300MHz, DMSO-d₆) δ10.91 (s, 1H), 9.28 (s, 1H), 8.43 (t, J=5.5 Hz, 1H), 8.09(d, J=5.0 Hz, 1H), 7.93 (br s, 2H), 7.66 (s, 1H), 7.62 (m, 1H), 7.43 (m,2H), 7.24 (d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.7 Hz), 4.62 (s, 2H), 3.79(t, 2H, J=5.2 Hz), 3.35 (q, 2H, J=5.4 Hz), 2.77 (d, J=4.8 Hz, 3H), 2.35(s, 3H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₉H₂₆SN₆O₅:451.0 (M+H); found: 451.1. MS-MS of 451.1 peak gave 394.9(M-C(═NH)NCH₃).

EXAMPLE 104

[0609] 3-(Benzylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

[0610] The title compound was prepared in a manner analogous to Example103. ¹H-NMR (300 MHz, DMSO-d₆) δ10.89 (s, 1H), 8.57 (s, 1H), 8.47 (t,J=5.5 Hz, 1H), 8.09 (br s, 1H), 7.93 (s, 2H), 7.34 (m, 5H), 7.13 (d,J=7.5 Hz, 1H), 6.10 (d, J=7.7 Hz, 1H), 4.73 (s, 2H), 4.51 (s, 2H), 3.83(t, J=5.4 Hz, 2H), 3.41 (m, 2H), 2.77 (d, J=4.9 Hz, 3H), 2.25 (s, 3H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₉H₂₆N₆O₅S: 451.2 (M+H), 473.2 (M+Na); Found: 451.4, 473.5. MS-MSof 451.4 peak gave 394.9 (M-C(═NH)NCH₃).

EXAMPLE 105

[0611] 3-(3-Methylphenylsulfonyl)amino6-methyl-1-[(2-(N-methoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone

[0612] A suspension of3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone hydrochloride (0.2 g, 0.42 mmol), asprepared in step 5 of Example 5, in acetonitrile (10 mL) was treatedwith N,N-diisopropylethylamine (0.08 mL, 0.46 mmol) and dimethylpyrocarbonate (0.05 mL, 0.46 mmol). The reaction mixture was allowed tostir at room temperature overnight. An additional solvent,N,N-dimethylformamide (5 mL) was added to effect solution. Additionaldimethyl pyrocarbonate (0.30 mL, 2.76 mmol) was added and the reactionmixture was stirred for 2 days. The reaction mixture was evaporated todryness under high vacuum and the residue was purified on a silica gelcolumn (5 g SepPak) using 4% methanol in methylene chloride as elutingsolvent to give 0.071 g (29% yield) of desired product as a white solid.¹H-NMR (300 MHz, DMSO-d₆) δ9.65 (s, 1H), 9.30 (s, 1H), 8.28 (t, J=5.5Hz, 1H), 7.60-7.67 (m, 2H), 7.38-7.44 (m, 2H), 7.23 (d, J=7.5 Hz, 1H),6.20 (s, 2H), 6.06 (d, J=7.6 Hz, 1H), 4.61 (m, 2H), 3.73 (t, J=5.5 Hz,2H), 3.61 (s, 3H), 3.27-3.31 (m, 2H), 2.35 (s, 3H), 2.18 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₀H₂₆N₆O₇S: 495 (M+H); Found: 495.0.

EXAMPLE 106

[0613]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N′,N″-triethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone

[0614] To a solution of3-(3-methylphenyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone hydrochloride (237 mg, 0.5 mmol), asprepared in step 5 of Example 5, and N,N′-diiso-propylethylamine (180μL, 1.0 mmol) in N,N-dimethylformamide (10 mL) was added diethylpyrocarbonate (150 μL, 1.0 mmol). The mixture was stirred at ambienttemperature overnight. The N,N-dimethylformamide was evaporated underhigh vacuum, the residue was dissolved in methylene chloride (50 mL),washed with 10% citric acid (2×20 mL), brine (20 mL) and dried overNa₂SO₄. After evaporating the solvent, the residue was purified byWaters Sep-Pak (10 g, 30-40% ethyl acetate in methylene chloride) togive the title compound as a white solid (210 mg, 65%). ¹H-NMR (300 MHz,CDCl₃) δ9.33 (br s, 1H), 8.64 (s, 1H), 8.58 (br s, 1H), 7.97 (m, 2H),7.52 (d, J=7.5 Hz, 1H), 7.26 (m, 2H), 6.15 (d, J=7.7 Hz, 1H), 4.70-5.00(m, 2H), 4.40 (q, J=7.1 Hz, 2H), 4.21 (q, J=7.2 Hz, 2H), 4.07 (q, J=7.1Hz, 2H), 3.85 (m, 2H), 3.54 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 1.41(t, J=7.1 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.09 (t, J=7.1 Hz, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₇H₃₆N₆O₁₁S: 653.0 (M+H); Found: 653.0.

EXAMPLE 107

[0615]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N′-diethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone

[0616] and3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N-ethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone

[0617] To a solution of3-(3-methylphenyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone hydrochloride (475 mg, 1.0 mmol), asprepared in step 5 of Example 5, and N-methylmorpholine (220 μL, 2.0mmol) in N,N′-dimethylformamide (10 mL) was added diethyl pyrocarbonate(150 μL, 1.0 mmol). The mixture was stirred at ambient temperatureovernight. The N,N-dimethylformamide was evaporated under high vacuum,the residue was dissolved in methylene chloride (50 mL), washed with 10%citric acid (2×20 mL), brine (20 mL) and dried over Na₂SO₄. Afterevaporating the solvent, the residue was purified by Waters Sep-Pak (10g, 30-40% ethyl acetate in methylene chloride then 25 methanol inmethylene chloride) to give3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N′-diethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone as a white solid (320 mg, 55%). ¹H-NMR(300 MHz, CDCl₃) δ9.34 (br s, 1H), 8.74 (s, 1H), 8.59 (br s, 1H), 7.67(s, 1H), 7.64 (m, 1H), 7.60 (s, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.32 (d,J=5.2 Hz, 2H), 6.01 (d, J=7.6 Hz, 1H), 4.97+4.67 (m, 2H), 4.40 (q, J=7.1Hz, 4.14 (q, J=7.1 Hz, 2H), 4.36+3.91 (m, 2H), 3.52 (m, 2H), 2.38 (s,3H), 2.26 (s, 3H), 1.42 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₄H₃₂N₆O₉S: 581.2 (M+H); Found: 581.0.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N-ethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone as a white solid (80 mg, 16%). ¹H-NMR(300 MHz, CDCl₃) δ8.30 (br s, 1H), 8.17 (br s, 1H), 7.56 (m, 4H), 7.33(m, 2H), 6.14 (d, J=7.7 Hz, 1H), 5.77 (br s, 2H), 4.67 (br s, 2H), 4.35(q, J=7.1 Hz, 2H), 3.85 (m, 2H), 3.42 (m, 2H), 2.44 (s, 3H), 2.36 (s,3H), 1.39 (t, J=7.1 Hz, 3H). Mass spectrum (LCMS, ESI) calcd. forC₂₁H₂₈N₆O₇S: 509.1 (M+H); Found: 509.1.

EXAMPLE 108

[0618]3-(3-Methylphenylsulfonyl)amino-6-methyl-1-{[2-N″-(3-phenylpropyl)guanidinooxyethyl]aminocarbonylmethyl}-2-pyridinone hydrochloride

[0619] The title compound was prepared in a manner analogous to Example99. ¹H NMR (300 MHz, DMSO-d₆) δ9.25 (s, 1H0, 8.65 (t, 1H, J=5 Hz), 8.03(br s, 3H), 7.78 (br s, 1H), 7.64 (m, 2H), 7.26 (m, 10H), 6.07 (m, 1H),4.63 (br s, 2H), 3.89 (t, 2H, J=4.9 Hz), 3.71 (t, 2H, J=7 Hz), 2.58 (m,2H), 2.34 (s, 3H), 2.16 (s, 3H), 1.87 (m, 2H). Mass spectrum (LCMS, ESI)calcd. for C₂₇H₃₄N₆O₅S: 555.0 (M+H). Found: 555.1. MS-MS of 555.1 peakgave 513.0 (M-C(═NH)NH).

EXAMPLE 109

[0620] Tablet Preparation

[0621] Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of thefollowing active compounds are prepared as illustrated below:

[0622] a. 3-benzylsulfonylamino-6-methyl-1-[(3-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinone; and

[0623] b. 3-benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone TABLET FOR DOSES CONTAINING FROM25-100 MG OF THE ACTIVE COMPOUND Amount-mg Active Compound 25.0 50.0100.00 Microcrystalline cellulose 37.25 100.0 200.0 Modified food cornstarch 37.25 4.25 8.5 Magnesium stearate 0.50 0.75 1.5

[0624] All of the active compound, cellulose, and a portion of the cornstarch are mixed and granulated to 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and the magnesium stearate. The resulting granulation is thencompressed into tablets containing 25.0, 50.0, and 100.0 mg,respectively, of active ingredient per tablet.

EXAMPLE 110

[0625] Intravenous Solution Preparation

[0626] An intravenous dosage form of the above-indicated activecompounds is prepared as follows: Active Compound 0.5-10.0 mg SodiumCitrate 5-50 mg Citric Acid 1-15 mg Sodium Chloride 1-8 mg Water forInjection (USP) q.s. to 1 ml

[0627] Utilizing the above quantities, the active compound is dissolvedat room temperature in a previously prepared solution of sodiumchloride, citric acid, and sodium citrate in Water for Injection (USP,see page 1636 of United States Pharmacopeia/National Formulary for 1995,published by United States Pharmacopeial Convention, Inc., Rockville,Ma. (1994).

EXAMPLE 111

[0628] In vitro Inhibition of Purified Enzymes

[0629] Reagents: All buffer salts were obtained from Sigma ChemicalCompany (St. Louis, Mo.), and were of the highest purity available. Theenzyme substrates, N-benzoyl-Phe-Val-Arg-p-nitroanilide (Sigma B7632),N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride (Sigma B2291),N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide (Sigma T6 140),N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (Sigma S7388) andN-CBZ-Val-Gly-Arg-p-nitroanilide (Sigma C7271) were obtained from Sigma.N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide (BACHEM L-1720) andN-succinyl-Ala-Ala-Pro-Val-p-nitroanilide (BACHEM L-1770) were obtainedfrom BACHEM (King of Prussia, Pa.).

[0630] Human α-thrombin, human factor Xa and human plasmin were obtainedfrom Enzyme Research Laboratories (South Bend, Indiana). Bovineα-chymotrypsin (Sigma C4129), bovine trypsin (Sigma T8642) and humankidney cell urokinase (Sigma U5004) were obtained from Sigma. Humanleukocyte elastase was obtained from Elastin Products (Pacific, Mo.).K_(i) Determinations: All assays are based on the ability of the testcompound to inhibit the enzyme catalyzed hydrolysis of a peptidep-nitroanilide substrate. In atypical K_(i) determination, substrate isprepared in DMSO, and diluted into an assay buffer consisting of 50 mMHEPES, 200 mM NaCl, pH 7.5. The final concentrations for each of thesubstrates is listed below. In general, substrate concentrations arelower than the experimentally determined value for K_(m). Test compoundsare prepared as a 1.0 mg/ml solution in DMSO. Dilutions are prepared inDMSO yielding 8 final concentrations encompassing a 200 foldconcentration range. Enzyme solutions are prepared at the concentrationslisted below in assay buffer.

[0631] In a typical K_(i) determination, into each well of a 96 wellplate is pipetted 280 mL of substrate solution, 10 mL of test compoundsolution, and the plate allowed to thermally equilibrate at 37° C. in aMolecular Devices plate reader for >15 minutes. Reactions were initiatedby the addition of a 10 mL aliquot of enzyme and the absorbance increaseat 405 nm is recorded for 15 minutes. Data corresponding to less than10% of the total substrate hydrolysis were used in the calculations. Theratio of the velocity (rate of change in absorbance as a function oftime) for a sample containing no test compound is divided by thevelocity of a sample containing test compound, and is plotted as afunction of test compound concentration. The data are fit to a linearregression, and the value of the slope of the line calculated. Theinverse of the slope is the experimentally determined K_(i) value.

[0632] Thrombin: Thrombin activity was assessed as the ability tohydrolyze the substrate N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide.Substrate solutions were prepared at a concentration of 32 mM (32mM<<Km=180 mM) in assay buffer. Final DMSO concentration was 4.3%.Purified human a-thrombin was diluted into assay buffer to aconcentration of 15 nM. Final reagent concentrations were:[thrombin]=0.5 nM, [substrateN-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide]=32 mM.

[0633] Factor X [FXa]: FXa activity was assessed as the ability tohydrolyze the substrate N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilidehydrochloride. Substrate solutions were prepared at a concentration of51 mM (51<<K_(m)=1.3 mM) in assay buffer. Final DMSO concentration was4.3%. Purified activated human Factor X was diluted into assay buffer toa concentration of 300 nM. Final reagent concentrations were: [FXa]=10nM, [N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride]=51 mM.

[0634] Plasmin: Plasmin activity was assessed as the ability tohydrolyze the N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide. Substrate solutionswere prepared at a concentration of 37 mM (37 mM<<K_(m)=243 mM) in assaybuffer. Final DMSO concentration was 4.3%. Purified human plasmin wasdiluted into assay buffer to a concentration of 240 nM. Final reagentconcentrations were: [Plasmin]=8 nM,[N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide]=37 mM.

[0635] Chymotrypsin: Chymotrypsin activity was assessed as the abilityto hydrolyze N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide. Substratesolutions were prepared at a concentration of 14 mM (14 mM<<K_(m)=62 mM)in assay buffer. Final DMSO concentration was 4.3%. Purified bovinechymotrypsin was diluted into assay buffer to a concentration of 81 nM.Final reagent concentrations were: [Chymotrypsin]=2.7 nM,[N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide]=14 mM.

[0636] Trypsin: Trypsin activity was assessed as the ability tohydrolyze N-benzoyl-Phe-Val-Arg-p-nitroanilide. Substrate solutions wereprepared at a concentration of 13 mM (13 mM<<K_(m)=291 mM) in assaybuffer. Final DMSO concentration was 4.3%. Purified bovine trypsin wasdiluted into assay buffer to a concentration of 120 nM. Final reagentconcentrations were: [Trypsin]=4 nM,[N-benzoyl-Phe-Val-Arg-p-nitroanilide]=13 mM.

[0637] Elastase: Elastase activity was assessed as the ability tohydrolyze N-succinyl-Ala-Ala-Pro-Val-p-nitroanilide. Substrate solutionswere prepared at a concentration of 19 mM (19 mM<<K_(m)=89 mM) in assaybuffer. Final DMSO concentration was 4.3%. Purified human leukocyteelastase was diluted into assay buffer to a concentration of 750 nM.Final reagent concentrations were: [Elastase]=25 nM,[N-succinyl-Ala-Ala-Pro-Val-p-nitroanilide]=19 mM.

[0638] Urokinase: Urokinase activity was assessed as the ability tohydrolyze N-CBZ-Val-Gly-Arg-p-nitroanilide. Substrate solutions wereprepared at a concentration of 100 mM (100 mM<K_(m)=1.2mM) in assaybuffer. Final DMSO concentration was 4.3%. Purified human kidneyurokinase was diluted into assay buffer to a concentration of 1.2 mM.Final reagent concentrations were: [Urokinase]40 nM, and[N-CBZ-Val-Gly-Arg-p-nitroanilide]=100 mM.

[0639] The results of compounds of the invention are shown in thefollowing table. TABLE 1 Assay, K_(i) (nM) or (% Inhibition at (nM)) Eg.No. Thrombin FXa Chymo. Elastase Plasmin Trypsin 1 53 0@24,000 0@24,0000@24,000 0@24,000 0@24,000 2 7.9 24,000 14,000 0@24,500 0@24,5000@24,500 4 29 7,900 0@79,000 5 6.0 0@24,600 0@24,600 0@24,600 0@24,600 843 0@56,000 0@56,000 16 2.0 2,200 0@19,000 4,000 24 2.0 2,200 0@18,0007,600 30 61 7.600 0@23,500 0@23,500 0@23,500 0@23,500 38 51 420 0@20,0000@20,000 0@20,000 0@20,000 55 220 2,100 2,300 71 580 8,700 0@12,0000@12,000 0@12,000 0@12,000 85 290 1,300 0@18,000 0@18,000 0@18,000 1,600

[0640] Chymo=chymotrypsin

[0641] The results indicate that the compounds of the present inventionare potent and highly selective inhibitors of thrombin.

[0642] Having now fully described this invention, it will be understoodto those of ordinary skill in the art that the same can be performedwithin a wide and equivalent range of conditions, formulations, andother parameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

What is claimed is:
 1. A compound having the Formula VII:

or a solvate, hydrate or pharmaceutically acceptable salt thereof;wherein: R¹ is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl,aryl, aralkyl, heterocycle or heterocycloalkyl, any of which may beoptionally substituted; Z is —SO₂—, —OCO—, —CO—, —NR²CO— or a covalentbond, where R² is hydrogen, alkyl, aralkyl, aryl, hydroxy(C₂₋₁₀)alkyl,amino(C₂₋₁₀)alkyl, monoalkylamino(C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkylor carboxyalkyl; Het is selected from the group consisting of

where R³, R⁴ and R⁵ are independently hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen,hydroxyalkyl, cyano, nitro, carboxamido, —CO₂R^(x), —CH₂OR^(x) or—OR^(x), where R^(x), in each instance, is independently one ofhydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groupsmay optionally have one or more unsaturations, R⁶ is hydrogen, alkyl,aralkyl, aryl, cyano(C₂₋₁₀)alkyl, hydroxy(C₂₋₁₀)alkyl,alkoxy(C₂₋₁₀)alkyl, mono- and di-alkylamino(C₂₋₁₀)alkyl, orcarboxyalkyl; R⁷ is hydrogen, C₁₋₄alkyl, or C₂₋₄ alkenyl; R⁸ ishydrogen, alkyl, alkenyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,monoalkylamino (C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl or carboxyalkyl;R¹², R¹³, R¹⁴ and R¹⁵ are independently hydrogen, alkyl, aralkyl, aryl,hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl orcarboxyalkyl; or R¹² and R¹³ are taken together to form —(CH₂)_(y)—,where y is 2 to 7, while R¹⁴ and R¹⁵ are defined as above; or R¹⁴ andR¹⁵ are taken together to form —(CH₂)_(q)—, where q is 2 to 7,while R¹²and R¹³ are defined as above; or R¹² and R¹⁴ are taken together to form—(CH₂)_(r)—, where r is 0 (a bond) or 1 to 7, while R¹³ and R¹⁵ aredefined as above; X is oxygen or NR⁹, where R⁹ is hydrogen, alkyl,cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can beoptionally substituted with amino, monoalkylamino, dialkylamino, alkoxy,hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,aryl, heteroaryl, acylamino, cyano or trifluoromethyl; R^(a), R^(b) andR^(c) are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy,aralkoxy, alkoxycarbonyloxy, cyano or —CO₂R^(w), where R^(w) is alkyl,cycloalkyl, phenyl, benzyl,

where R^(d) and R^(c) are independently hydrogen, C₁₋₆alkyl, C₂₋₆,alkenyl or phenyl, R^(f) is hydrogen, C₁₋₆ alkyl, C₂₋₆, alkenyl orphenyl, R^(g) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, and R^(h)is aralkyl or C₁₋₆ alkyl; n is from zero to 8; and m is from zero to 6.2. A compound of claim 1, wherein C₆₋₁₀ ar(C₁₋₄) alkyl, C₆₋₁₀ aryl, C₄₋₇cycloalkyl(C₁₋₄)alkyl, heterocycle or heterocyclo(C₁₋₄)alkyl, any ofwhich is optionally substituted; and wherein the heterocycle of saidheterocycle or heterocyclo(C₁₋₄)alkyl is a 5- to 7-member mono-cyclic,or 9- to 10-member bi-cyclic heterocyclic ring that is saturated orunsaturated, and contains 1 to 3 heteroatoms selected from N, O and S.3. A compound of claim 2, wherein R¹ is C₆₋₁₀ ar(C₁₋₄) alkyl, C₆₋₁₀aryl, C₄₋₇ cycloalkyl(C₁₋₄)alkyl, any of which is optionally substitutedby 1-5 of hydroxy, nitro, trifluoromethyl, halogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₆₋₁₀aryl, C₁₋₆alkoxy, C₆₋₁₀ar(C₁₋₆)alkoxy, C₁₋₆aminoalkyl, C₁₋₆ aminoalkoxy, amino, mono(C₁₋₄)alkylamino,di(C₁₋₄)alkylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆ alkoxycarbonylamino,C₂₋₆ alkoxycarbonyl, carboxy, C₁₋₆ hydroxyalkyl, C₂₋₆ hydroxyalkoxy,(C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono- and di- C₁₋₄ alkylamino (C₂₋₆)alkoxy,C₂₋₁₀ mono(carboxyalkyl)amino, bis(C₂₋₁₀ carboxyalkyl) amino, C₆₋₁₄ar(C₁₋₆) alkoxycarbonyl, C₂₋₆ alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₂₋₆alkenylsulfonyl, C₂₋₆ alkynylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ar(C₁₋₆) alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonamido,C₆₋₁₀arylsulfonamido, C₆₋₁₀ ar(C₁₋₆) alkylsulfonamido, amidino,guanidino, C₁₋₆ alkyliminoamino, formyliminoamino, C₂₋₆ carboxyalkoxy,C₂₋₆ carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy, orperfluoroethoxy.
 4. A compound of claim 1, wherein Het is selected fromthe group consisting of:

where R³, R⁴ and R⁵ are independently hydrogen, C₁₋₄alkyl,C₃₋₇cycloalkyl, C₆₋₁₄aryl, especially C₆₋₁₀aryl, C₆₋₁₀ar(C₁₋₄)alkyl,trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamide,carboxy, alkoxycarbonyl, carboxymethyl, alkoxycarbonylmethyl, orcycloalkyloxycarbonyl.
 5. A compound of claim 4, wherein R³, R⁴ and R⁵are independently hydrogen, methyl, ethyl, propyl, chloro, bromo,trifluoromethyl, hydroxymethyl, methoxy, ethoxy, carboxamide, nitro,phenyl, cyclopropyl, hydroxy, isopropyl, methoxycarbonyl, ethoxycarbonyland benzyl.
 6. A compound of claim 1, wherein R³ and R⁴ groups areindependently hydrogen, C₁₋₁₂alkyl, or C₂₋₆alkenyl.
 7. A compound ofclaim 6, wherein R³ and R⁴ are hydrogen.
 8. A compound of claim 1,wherein R⁵ is hydrogen, halogen, C₁₋₅alkyl, C₃₋₆alkenyl, C₃₋₅cycloalkyl, trifluoromethyl, or C₁₋₄ alkoxy.
 9. A compound of claim 1,wherein Het is:

wherein R³ and R⁴ are independently selected to be hydrogen or methyl,and R⁵ is selected from the group consisting of hydrogen, methyl, ethyl,propenyl, allyl, propyl, isopropyl, butyl, R-sec-butyl, S-sec-butyl,isobutyl, 1-pentyl, R-2-pentyl, S-2-pentyl, 3-pentyl,S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl,R-1-(2-methyl)-butyl, cyclopentyl, 2-pyrolyl, 3-pyrolyl, 1-hexyl,S-2-hexyl, R-2-hexyl, R-3-hexyl, and S-3-hexyl.
 10. A compound of claim9, wherein Rs is hydrogen, methyl, ethyl, propyl or isopropyl.
 11. Acompound of claim 1, wherein Z is —SO₂— or a covalent bond.
 12. Acompound of claim 1, wherein R⁷ is hydrogen.
 13. A compound of claim 1,wherein X is oxygen.
 14. A compound of claim 1, wherein X is NR⁹.
 15. Acompound of claim 1, wherein R⁹ is hydrogen or C₁₋₆ alkyl, optionallysubstituted by one, two or three, preferably one, of amino,monoalkylamino, dialkylamino, alkoxy, hydroxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, carboalkoxy, phenyl, cyano,trifluoromethyl, acetylamino, pyridyl, thiophenyl, furyl, pyrrolyl orimidazolyl.
 16. A compound of claim 1, wherein R⁹ is hydrogen, methyl,ethyl, propyl, n-butyl, benzyl, phenethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, carboxymethyl or carboxyethyl.
 17. Acompound of claim 1, wherein R⁸ is hydrogen, C₁₋₆ alkyl or C₆₋₁₀ aryl(C₁₋₆)alkyl.
 18. A compound of claim 1, wherein R¹², R¹³, R¹⁴ and R¹⁵are independently one of hydrogen, C₁₋₆ alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl,C₆₋₁₀aryl, C₂₋₁₀ hydroxyalkyl or C₂₋₇ carboxyalkyl.
 19. A compound ofclaim 18, wherein R¹², R¹³, R¹⁴ and R¹⁵ are independently hydrogen,methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 2-carboxymethyl, 3-carboxyethyl and4-carboxypropyl.
 20. A compound of claim 1, wherein R^(a), R^(b) andR^(c) are independently hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, cyanoor —CO₂R^(w), where R^(w), in each instance, is preferably one ofC₁₋₄alkyl, C₄₋₇cycloalkyl or benzyl,

where R^(d), R^(e) and R^(g) are hydrogen, R^(f) is methyl, and R^(h) isbenzyl or tert-butyl.
 21. A compound of claim 20, wherein R^(a), R^(b)and R^(c) are hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy,methoxy, ethoxy, cyano, —CO₂CH₃, —CO₂CH₂CH₃ and —CO₂CH₂CH₂CH₃.
 22. Acompound of claim 21, wherein R^(a), R^(b) and R^(c) are each hydrogen.23. A compound of claim 1, wherein n is zero to 6, and m is zero to 4.24. A compound of claim 23, wherein n is zero to 4 and m is zero, 1 or2.
 25. A compound of claim 1, wherein: R¹ is C₆₋₁₀ar(C₁₋₄) alkyl,C₆₋₁₀aryl, C₄₋₇cycloalkyl(C₁₋₄)alkyl, any of which is optionallysubstituted by 1-5 of hydroxy, nitro, trifluoromethyl, halogen,C₁₋₆alkyl, C₆₋₁₀ aryl, C₁₋₆alkoxy, C₆₋₁₀ ar(C₁₋₆)alkoxy, C₁₋₆aminoalkyl, C₁₋₆ aminoalkoxy, amino, mono(C₁₋₄)alkylamino,di(C₁₋₄)alkylamino, C₂₋₆alkoxycarbonylamino, C₂₋₆alkoxycarbonyl carboxy,C₁₋₆hydroxyalkyl, C₂₋₆hydroxyalkoxy, (C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono- anddi- C₁₋₄alkylamino (C₂₋₆)alkoxy, C₂₋₁₀ mono(carboxyalkyl)amino,bis(C₂₋₁₀carboxyalkyl) amino, C₆₋₁₄ ar(C₁₋₆) alkoxycarbonyl, C₂₋₆alkynylcarbonyl, C₁₋₆alkylsulfonyl, C₂₋₆alkenylsulfonyl,C₂₋₆alkynlsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ ar(C₁₋₆) alkylsulfonyl,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonamido, C₆₋₁₀ arylsulfonamido,C₆₋₁₀ar(C₁₋₆) alkylsulfonamido, amidino, guanidino, C₁₋₆alkyliminoamino,formyliminoamino, C₂₋₆ carboxyalkoxy, C₂₋₆ carboxyalkyl,carboxyalkylamino, cyano, trifluoromethoxy, or perfluoroethoxy; Het is:

wherein R³ and R⁴ are independently selected to be hydrogen or methyl,and R⁵ is selected from the group consisting of hydrogen, methyl, ethyl,propenyl, allyl, propyl, isopropyl, butyl, R-sec-butyl, S-sec-butyl,isobutyl, 1-pentyl, R-2-pentyl, S-2-pentyl, 3-pentyl,S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl,R-1-(2-methyl)-butyl, cyclopentyl, 2-pyrolyl, 3-pyrolyl, 1-hexyl,S-2-hexyl, R-2-hexyl, R-3-hexyl, and S-3-hexyl; Z is —SO₂— or a covalentbond; R¹², R¹³, R¹⁴ and R¹⁵ are independently one of hydrogen, C₁₋₆alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl, C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl orC₂₋₇carboxyalkyl; X is oxygen; R^(g) is hydrogen, C₁₋₄, alkyl or C₆₋₁₀aryl (C₁₋₆)alkyl; R^(a), R^(b) and R^(c) are hydrogen, methyl, ethyl,propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, —CO₂CH₃, —CO₂CH₂CH₃and —CO₂CH₂CH₂CH₃; n is zero to 6, and m is zero to
 4. 26. A compound ofclaim 1, wherein Z is —SO₂—, R¹ is substituted or unsubstituted aryl oraralkyl, Het is

X is O, R⁸ is hydrogen, C₁₋₄ alkyl or C₆₋₁₀ aryl(C₁₋₆)alkyl, and R^(a),R^(b) and R^(c) are all hydrogen.
 27. A compound of claim 26, wherein R¹is substituted or unsubstituted benzyl or phenyl.
 28. A compound havingFormula VIII:

or a solvate, hydrate of pharmaceutically acceptable salt thereof,wherein Z′ is —OCO—, —CO—, —SO₂—, —NHCO—, or a covalent bond; R²¹ is:R²²(CH₂)_(k), where k is 0-4, (R²²)(OR²²)CH(CH₂)_(p), where p is 1-4,(R²²)₂CH(CH₂)_(k), where k is 0-4 and R²² can be the same or different,and wherein (R²²)₂ can also be a ring substituent on CH represented byC₃₋₇ cycloalkyl, C₇₋₁₂ bicyclic alkyl, or a 5- to 7-membered mono- or 9-to 10-membered bicyclic heterocyclic ring which can be saturated orunsaturated, and which contains from one to three heteroatoms selectedfrom the group consisting of N, O and S, and R²²O(CH₂)_(p), wherein p is1-4; R²² is hydrogen; phenyl, unsubstituted or substituted with one ormore of C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, trifluoromethyl, hydroxy, COOH,or CONH₂; naphthyl; biphenyl; a 5- to 7-membered mono- or a 9- to10-membered bicyclic heterocyclic ring which can be saturated orunsaturated, and which contains from one to three heteroatoms selectedfrom the group consisting of N, O and S; C₁₋₄ alkyl; C₃₋₇ cycloalkyl, orC₇₋₁₂ bicyclic alkyl; R²⁵ is hydrogen; C₁₋₄ alkyl; C₃₋₇ cycloalkyl, ortrifluoromethyl; R^(a), R^(b) and R^(c) are independently hydrogen,hydroxy, or cyano; R³², R³³, R³⁴ and R³⁵ are independently one ofhydrogen, C₁₋₆ alkyl, C₂₋₁₀ carboxyalkyl or C₂₋₁₀ hydroxyalkyl, or R³²and R³³ are taken together to form —(CH₂)_(y)— where y is 2 to 5, whileR³⁴ and R³⁵ are defined as above; or R³⁴ and R³⁵ are taken together toform —(CH₂)_(q)—, where q is 2 to 5, while R³² and R³³ are defined asabove; or R³² and R³⁴ are taken together to form —(CH₂)_(r)—, where r is0 (a bond) or 1-4, while R³³ and R³⁵ are defined as above; R²⁸ ishydrogen, C₁₋₄ alkyl or C₆₋₁₀ aryl (C₁₋₄)alkyl X′ is 0; n is from zeroto 4; and m is zero to
 2. 29. A compound of claim 28, wherein Z′ is acovalent bond or —SO₂—.
 30. A compound of claim 28, wherein R²¹ isR²²(CH₂)_(k), (R²²)₂CH(CH₂)_(k), phenyl, or (phenyl)₂—CH.
 31. A compoundof claim 28, wherein R²⁵ is C₁₋₄ alkyl
 32. A compound of claim 31,wherein R²⁵ is methyl.
 33. A compound of claim 28, wherein R²⁸ ishydrogen, C₁₋₄ alkyl, or benzyl.
 34. A compound of claim 1, wherein R¹is phenyl, benzyl, 1-naphtylmethyl, 2-naphthylmethyl, pyridyl,pyridylmethyl, quinolinyl or quinolinylmethyl, any of which isoptionally substituted by 1-5 of chloro, methoxy, methyl,trifluoromethyl, cyano, nitro, methylsulfonyl, amino or dimethylamino.35. A compound of claim 1, wherein R¹ is 8-quinolinyl,5-methyl-8-quinolinyl, 8-quinolinylmethyl, 5-methyl-8-quinolinylmethyl,4-benzo-2, 1,3-thiadiazolyl, 5-chloro-2-thiophenyl,5-chloro-1,3-dimethyl-4-pyrazolyl, pyridyl, isoquinolinyl,pyridylmethyl, isoquinolinylmethyl, tetrahydroquinolinyl andtetrahydroquinolinylmethyl.
 36. A compound of claim 1, wherein m and nare each zero and R¹², R¹³, R¹⁴and R¹⁵ are each hydrogen.
 37. A compoundof claim 1, which is one of:3-benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-methyl-1[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-benzylsulfonylamino-6-methyl-1-[(1-(1-guanidinooxymethyl)cyclopropyl)aminocarbonylmethyl]-2-pyridinone;3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-iodobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-bromobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)amninocarbonylmethyl]-2-pyridinone;3-(4-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-chloro-6-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(2-fluorobenzylsulfonyl)amino-6-methyl-(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(4-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone, 3-(2,3-dichlorobenzylsulfonyl)amino-6-methyl-[2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3,4-difluorobenzylsulfonyl)amino-6-methyl-1-[2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2,4-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2,5-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3,4-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(1-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-methylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-phenysulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(4-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(4-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)arminocarbonylmethyl]-2-pyridinone;3-(4-ethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-isopropyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-ethyl-1-[2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-propyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-N″-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-methyl-1-[2-N″-butylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-methyl-1-{[2-N″-(3-phenylpropyl)guanidinooxyethyl]aminocarbonylmethyl}-2-pyridinone;and pharmaceutically acceptable salts thereof
 38. A pharmaceuticalcomposition for inhibiting proteolysis in a mammal, comprising an amountof a compound of any one of claims effective to inhibit proteolysis, anda pharmaceutically acceptable carrier or diluent.
 39. The pharmaceuticalcomposition of claim 38, comprising an amount of said compound effectiveto inhibit a trypsin-like protease.
 40. A method of inhibitingproteolysis in a mammal, comprising administering to the mammal acomposition of claim
 38. 41. The method of claim 39, wherein atrypsin-like protease is inhibited.
 42. A method of treatingpancreatitis, thrombosis, ischemia, stroke, restenosis, emphysema orinflammation in a mammal, comprising administering to the mammal acomposition of claim
 38. 43. A method of inhibiting thrombin-inducedplatelet aggregation and clotting of fibrinogen in plasma, comprisingadministering to the mammal a composition of claim
 38. 44. A method forinhibiting thrombin in blood comprising adding to the blood a compoundof claim
 1. 45. A method for inhibiting formation of blood plateletaggregates in blood comprising adding to the blood a compound ofclaim
 1. 46. A method for inhibiting thrombus formation in bloodcomprising adding to the blood a compound of claim
 1. 47. In a deviceused in blood collection, blood circulation, and blood storage whereinsaid device includes an effective amount of a thrombin inhibitingcompound or macromolecule as an anticoagulant, either embedded in, orphysically linked to, one or more materials that form the structure ofsaid device, the improvement comprising employing as said thrombininhibitor one or more compounds as claimed in claim
 1. 48. The device ofclaim 46, wherein said device is a catheter, blood dialysis machine,blood collection syringe, blood collection tube, blood line orextracorporeal blood circuit.
 49. The device of claim 46, wherein saiddevice is a stent that can be surgically inserted into a mammal.
 50. Aprocess for preparing an alkoxyguanidine compound of claim 1,comprising: reacting a compound of Formula IX:

or a salt thereof, with a compound of Formula X:

where R³, R⁴, R⁵, R¹², R¹³, R¹⁴, R¹⁵, R^(a), R^(b), R^(c), n and m areas defined in claim 1, and R⁵¹ is hydrogen or R¹—Z—, where R¹ and Z areas defined in claim 1, and provided that R^(a), R^(b) and R^(c) are nothydrogen.